Gastro-resistant controlled release oral dosage forms

ABSTRACT

This disclosure relates to gastro-resistant, controlled release dosage forms comprising Compound (I): 
                         
or a pharmaceutically acceptable salt and/or solvate thereof, the pharmacokinetic properties of these dosage forms, and the preparation of the same. The novel dosage forms disclosed herein are useful in reducing the risk of QT prolongation in a subject and in treating a disorder in a subject in need thereof, e.g., a subject diagnosed with schizophrenia, for example, in treating the negative symptoms in a subject diagnosed with schizophrenia having the CYP2D6 EM genotype.

RELATED APPLICATIONS

This application claims priority to, and the benefit of, U.S.Provisional Application No. 62/523,204, filed Jun. 21, 2017. Thecontents of which are incorporated herein by reference in theirentirety.

FIELD OF THE DISCLOSURE

The present disclosure relates generally to oral gastro-resistant (GR)controlled release (CR) dosage forms that reduce the risk of QTprolongation in patients treated with the compound identified as1H-Isoindol-1-one,2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-,hydrochloride, hydrate (1:1:2), and to the use of these dosage forms fortreating schizophrenia and other diseases.

BACKGROUND

The QT interval is a measurement of the duration of ventricular de- andrepolarization. Prolongation of the QT interval, referred to as QTprolongation, can result in increased risk for ventricular arrhythmias,including torsades de pointes (TdP). Since a number of drugs have beenshown to induce QT prolongation, development of new drugs typicallyincludes assessment of their QT prolongation potential.

An investigational medicine, roluperidone hydrochloride, with the codename MIN-101 is being developed by Minerva Neurosciences, Inc. (Waltham,Mass.) for treating negative symptoms in schizophrenia patients. Theactive ingredient in MIN-101 (previously known as CYR-101 and MT-210)has the chemical name 1H-Isoindol-1-one,2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-,hydrochloride, hydrate (1:1:2). Formula I below shows the structure ofthe free base (Compound (I)):

As disclosed in U.S. Pat. No. 9,458,130, the contents of which areincorporated herein in their entirety, QT prolongation in patientstreated with MIN-101 has been observed and appears to be related toplasma levels of Compound (I) and more specifically to a metaboliteidentified as BFB-520. The '130 patent discloses that QT prolongationinduced by administration of MIN-101 can be reduced by administeringthis agent in a modified release (MR) formulation that provides amaximum plasma concentration (C_(max)) of Compound (I) and BFB-520 below80 ng/mL and 12 ng/mL, respectively. However, a need exists for aformulation that further reduces the potential for QT prolongation afteroral administration of MIN-101 in either a fasted state or a fed state,while maintaining a therapeutically effective level of Compound (I)throughout a dosing interval.

SUMMARY

The present disclosure is based, in part, on the finding that minimizingthe release of Compound (I) during the first four hours after oraladministration of a dosage form comprising Compound (I) is a key factorfor maintaining low plasma levels of BFB-520.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

i. about 2 mg to about 200 mg of Compound (I), or an equivalent amountof a pharmaceutically acceptable salt and/or solvate thereof; and

ii. at least one controlled release agent.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

i. about 2 mg to about 200 mg of Compound (I), or an equivalent amountof a pharmaceutically acceptable salt and/or solvate thereof; and

ii. at least one controlled release agent;

wherein the dosage form produces, upon oral administration to thesubject, a plasma pharmacokinetic profile for Compound (I) whichcomprises a T_(max) between about 4 hours and about 22 hours.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

i. about 4 mg to about 100 mg of Compound (I), or an equivalent amountof a pharmaceutically acceptable salt and/or solvate thereof; and

ii. at least one controlled release agent.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

i. about 4 mg to about 100 mg of Compound (I), or an equivalent amountof a pharmaceutically acceptable salt and/or solvate thereof; and

ii. at least one controlled release agent;

wherein the dosage form produces, upon oral administration to thesubject, a plasma pharmacokinetic profile for Compound (I) whichcomprises a T_(max) between about 1 hours and about 22 hours.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

i. about 4 mg to about 100 mg of Compound (I), or an equivalent amountof a pharmaceutically acceptable salt and/or solvate thereof; and

ii. at least one controlled release agent;

wherein the dosage form produces, upon oral administration to thesubject, a plasma pharmacokinetic profile for Compound (I) whichcomprises a T_(max) between about 1.5 hours and about 22 hours.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

i. about 4 mg to about 100 mg of Compound (I), or an equivalent amountof a pharmaceutically acceptable salt and/or solvate thereof; and

ii. at least one controlled release agent;

wherein the dosage form produces, upon oral administration to thesubject, a plasma pharmacokinetic profile for Compound (I) whichcomprises a T_(max) between about 2 hours and about 22 hours.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

i. about 4 mg to about 100 mg of Compound (I), or an equivalent amountof a pharmaceutically acceptable salt and/or solvate thereof; and

ii. at least one controlled release agent;

wherein the dosage form produces, upon oral administration to thesubject, a plasma pharmacokinetic profile for Compound (I) whichcomprises a T_(max) between about 2.5 hours and about 22 hours.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

i. about 4 mg to about 100 mg of Compound (I), or an equivalent amountof a pharmaceutically acceptable salt and/or solvate thereof; and

ii. at least one controlled release agent;

wherein the dosage form produces, upon oral administration to thesubject, a plasma pharmacokinetic profile for Compound (I) whichcomprises a T_(max) between about 3 hours and about 22 hours.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

i. about 4 mg to about 100 mg of Compound (I), or an equivalent amountof a pharmaceutically acceptable salt and/or solvate thereof; and

ii. at least one controlled release agent;

wherein the dosage form produces, upon oral administration to thesubject, a plasma pharmacokinetic profile for Compound (I) whichcomprises a T_(max) between about 3.5 hours and about 22 hours.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

i. about 4 mg to about 100 mg of Compound (I), or an equivalent amountof a pharmaceutically acceptable salt and/or solvate thereof; and

ii. at least one controlled release agent;

wherein the dosage form produces, upon oral administration to thesubject, a plasma pharmacokinetic profile for Compound (I) whichcomprises a T_(max) between about 4 hours and about 22 hours.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising Compound (I), wherein theamount of Compound (I) is 4 mg to 8 mg, 8 mg to 16 mg, 16 mg to 32 mg,32 mg to 40 mg, 40 mg to 64 mg, 64 mg to 80 mg, or 80 mg to 100 mg.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising Compound (I), wherein theamount of Compound (I) is 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, or 100 mg.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising Compound (I), wherein theamount of Compound (I) is 4 mg, 8 mg, 16 mg, 24 mg, 32 mg, 40 mg, 64 mg,80 mg, 96 mg, or 100 mg.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

i. about 32 mg of Compound (I), or an equivalent amount of apharmaceutically acceptable salt and/or solvate thereof; and

ii. at least one controlled release agent.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

i. about 32 mg of Compound (I), or an equivalent amount of apharmaceutically acceptable salt and/or solvate thereof; and

ii. at least one controlled release agent;

wherein the dosage form produces, upon oral administration to thesubject, a plasma pharmacokinetic profile for Compound (I) whichcomprises a T_(max) between about 4 hours and about 22 hours.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

i. about 64 of Compound (I), or an equivalent amount of apharmaceutically acceptable salt and/or solvate thereof; and

ii. at least one controlled release agent.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

i. about 64 mg of Compound (I), or an equivalent amount of apharmaceutically acceptable salt and/or solvate thereof; and

ii. at least one controlled release agent;

wherein the dosage form produces, upon oral administration to thesubject, a plasma pharmacokinetic profile for Compound (I) whichcomprises a T_(max) between about 4 hours and about 22 hours.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 32 mg and theAUC_(0-4 H) of Compound (I) is less than about 68 h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 32 mg and theC_(max) of Compound (I) is less than about 16 ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 32 mg and theC_(max) of Compound (I) is less than about 17 ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 32 mg and theC_(max) of Compound (I) is less than about 18 ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 32 mg and theC_(max) of Compound (I) is less than about 19 ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 32 mg and theC_(max) of Compound (I) is less than about 20 ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 32 mg and theC_(max) of Compound (I) is less than about 21 ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 32 mg and theC_(max) of Compound (I) is less than about 22 ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 32 mg and theC_(max) of Compound (I) is less than about 23 ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 32 mg and theAUC_(0-24 hr) of Compound (I) is between about 50 h*ng/mL to about 400h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 32 mg and theAUC_(0-24 hr) of Compound (I) is between about 75 h*ng/mL to about 350h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 32 mg and theAUC_(0-24 hr) of Compound (I) is between about 75 h*ng/mL to about 300h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 32 mg and theAUC_(0-24 hr) of Compound (I) is between about 100 h*ng/mL to about 300h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 32 mg and the plasmapharmacokinetic profile for the BFB-520 metabolite of Compound (I)comprises a C_(max) that is below 3.0 ng/mL, below 2.5 ng/mL, below 2.0ng/mL, below 1.5 ng/mL or below 1.0 ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 64 mg and theAUC_(0-4 H) of Compound (I) is less than about 50 h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 64 mg and theAUC_(0-4 H) of Compound (I) is less than about 60 h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 64 mg and theAUC_(0-4 H) of Compound (I) is less than about 70 h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 64 mg and theAUC_(0-4 H) of Compound (I) is less than about 80 h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 64 mg and theAUC_(0-4 H) of Compound (I) is less than about 90 h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 64 mg and theAUC_(0-4 H) of Compound (I) is less than about 100 h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 64 mg and theAUC_(0-4 H) of Compound (I) is less than about 110 h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 64 mg and theAUC_(0-4 H) of Compound (I) is less than about 120 h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 64 mg and theAUC_(0-4 H) of Compound (I) is less than about 130 h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 64 mg and theC_(max) of Compound (I) is less than about 36 ng/mL or less than about25 ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 64 mg and theAUC_(0-24 hr) of Compound (I) is between about 200 h*ng/mL to about 600h*ng/mL.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage forms comprising Compound (I) disclosedherein, wherein the amount of Compound (I) is about 64 mg and the plasmapharmacokinetic profile for the BFB-520 metabolite of Compound (I)comprises a C_(max) that is below 4.0 ng/mL, below 3.5 ng/mL, below 3.0ng/mL, or below 2.5 ng/mL.

In one embodiment, the gastro-resistant, controlled release dosage formsdisclosed herein are in the form of a tablet which comprises a coretablet and an enteric coating.

In one embodiment, the core tablet of the gastro-resistant, controlledrelease dosage forms disclosed herein comprises Compound (I), or apharmaceutically acceptable salt and/or solvate thereof, and acontrolled release agent.

In one embodiment, the core tablet of the gastro-resistant, controlledrelease dosage forms disclosed herein comprises Compound (I), or apharmaceutically acceptable salt and/or solvate thereof, a controlledrelease agent, a filler, a glidant, and a lubricant.

In one embodiment, the core tablet of the gastro-resistant, controlledrelease dosage forms disclosed herein comprises Compound (I), or apharmaceutically acceptable salt and/or solvate thereof, a controlledrelease agent, a filler, a glidant, a lubricant and a coating.

In one embodiment, the controlled release agent in the core tablet ofthe gastro-resistant, controlled release dosage forms disclosed hereincomprises one or more hypromelloses.

In one embodiment, the controlled release agent in the core tablet ofthe gastro-resistant, controlled release dosage forms disclosed hereincomprises one or more hypromelloses selected from the group consistingof Metolose® 90SH K15M 100 SR, Metolose® 90SH 100 SR, Methocel™ K100MCR, Methocel™ K15M CR, Methocel™ K4M CR, and Methocel™ K100LV CR, orequivalent grade.

In one embodiment, the controlled release agent in the core tablet ofthe gastro-resistant, controlled release dosage forms disclosed hereincomprises a mixture of (i) a low viscosity hypromellose with a viscosityof between about 15 millipascal-seconds (mPa·s) to about 100 mPa·s and(ii) a high viscosity hypromellose with a viscosity of about 100,000mPa·s, wherein each of the low and high viscosity hypromelloses is acontrolled release or sustained-release grade and is furthercharacterized by a methoxy content of 19.0% to 24.0% and ahydroxypropoxy content of 4.0% to 12.0%.

In one embodiment, the glidant in the core tablet of thegastro-resistant, controlled release dosage forms disclosed herein issilica colloidal anhydrous.

In one embodiment, the lubricant in the core tablet of thegastro-resistant, controlled release dosage forms disclosed herein ismagnesium stearate.

In one embodiment, the enteric coating of the gastro-resistant,controlled release dosage forms disclosed herein comprises at least onepolymeric controlled release agent with a dissolution property ofgreater than pH 5.5, 6.0 or 6.5, and an anti-tacking agent.

In one embodiment, the enteric coating of the gastro-resistant,controlled release dosage forms disclosed herein further comprises aplasticizer.

In one embodiment, the polymeric controlled release agent of the entericcoating of the gastro-resistant, controlled release dosage formsdisclosed herein comprises Eudragit L30D55.

In one embodiment, the anti-tacking agent of the enteric coating of thegastro-resistant, controlled release dosage forms disclosed herein isPlasacryl HTP20.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

about 7 to about 17% w/w compound (I), or a pharmaceutically acceptablesalt and/or solvate thereof;

about 4 to about 14% w/w hypromellose (Metolose® 90SH K15M 100 SR);

about 17 to about 27% w/w hypromellose (Methocel™ K100M CR);

about 25 to about 35% w/w microcrystalline cellulose;

about 13 to about 23% w/w lactose monohydrate

about 0.1 to about 4% w/w silica colloidal anhydrous;

about 0.1 to about 4% magnesium stearate;

about 1 to about 10% w/w Eudragit L30D55; and

about 0.5 to about 5% w/w Plasacryl HTP20.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

about 12% w/w Compound (I), or a pharmaceutically acceptable salt and/orsolvate thereof;

about 9% w/w hypromellose (Metolose® 90SH K15M 100 SR);

about 23% w/w hypromellose (Methocel™ K100M CR);

about 30% w/w microcrystalline cellulose;

about 19% w/w lactose monohydrate

about 0.5% w/w silica colloidal anhydrous;

about 1% magnesium stearate;

about 5% w/w Eudragit L30D55; and

about 1% w/w Plasacryl HTP20.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

about 7 to about 17% w/w compound (I), or a pharmaceutically acceptablesalt and/or solvate thereof;

about 4 to about 14% w/w hypromellose (Methocel™ K15M CR);

about 17 to about 27% w/w hypromellose (Methocel™ K100M CR);

about 25 to about 35% w/w microcrystalline cellulose;

about 13 to about 23% w/w lactose monohydrate;

about 0.1 to about 4% w/w silica colloidal anhydrous;

about 0.1 to about 4% w/w magnesium stearate;

about 1 to about 10% Eudragit L30D55;

about 0.5 to about 5% w/w Plasacryl HTP20; and

about 0.5 to about 5% w/w Surelease E-7-19040.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

about 12% w/w Compound (I), or a pharmaceutically acceptable salt and/orsolvate thereof;

about 9% w/w hypromellose (Methocel™ K15M CR);

about 23% w/w hypromellose (Methocel™ K100M CR);

about 30% w/w microcrystalline cellulose;

about 19% w/w lactose monohydrate;

about 0.5% w/w silica colloidal anhydrous;

about 1% w/w magnesium stearate;

about 5% w/w Eudragit L30D55;

about 1% w/w Plasacryl HTP20; and

about 1% w/w Surelease E-7-19040.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

about 7 to about 17% w/w Compound (I), or a pharmaceutically acceptablesalt and/or solvate thereof;

about 4 to about 14% w/w hypromellose (Methocel™ K100LV CR);

about 17 to about 27% w/w hypromellose (Methocel™ K100M CR);

about 25 to about 35% w/w microcrystalline cellulose;

about 13 to about 23% w/w lactose monohydrate

about 0.1 to about 4% w/w silica colloidal anhydrous;

about 0.1 to about 4% magnesium stearate;

about 1 to about 10% w/w Eudragit L30D55; and

about 0.5 to about 5% w/w Plasacryl HTP20.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

about 12% w/w Compound (I), or a pharmaceutically acceptable salt and/orsolvate thereof;

about 9% w/w hypromellose (Methocel™ K100LV CR);

about 23% w/w hypromellose (Methocel™ K100M CR);

about 30% w/w microcrystalline cellulose;

about 19% w/w lactose monohydrate;

about 0.5% w/w silica colloidal anhydrous;

about 0.5% w/w magnesium stearate;

about 5% w/w Eudragit L30D55; and

about 1% w/w Plasacryl HTP20.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

about 12% w/w Compound (I), or a pharmaceutically acceptable salt and/orsolvate thereof;

about 9% w/w hypromellose (Methocel™ K100LV CR);

about 23% w/w hypromellose (Methocel™ K100M CR);

about 30% w/w microcrystalline cellulose;

about 19% w/w lactose monohydrate;

about 0.5% w/w silica colloidal anhydrous;

about 1% w/w magnesium stearate;

about 5% w/w Eudragit L30D55; and

about 1% w/w Plasacryl HTP20.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

about 19 to about 29% w/w Compound (I), or a pharmaceutically acceptablesalt and/or solvate thereof;

about 4 to about 14% w/w hypromellose (Methocel™ K100LV CR);

about 17 to about 27% w/w hypromellose (Methocel™ K100M CR);

about 19 to about 29% w/w microcrystalline cellulose;

about 8 to about 18% w/w lactose monohydrate

about 0.1 to about 4% w/w silica colloidal anhydrous;

about 0.1 to about 4% magnesium stearate;

about 1 to about 10% w/w Eudragit L30D55; and

about 0.5 to about 5% w/w Plasacryl HTP20.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

about 24% w/w Compound (I), or a pharmaceutically acceptable salt and/orsolvate thereof;

about 9% w/w hypromellose (Methocel™ K100LV CR);

about 23% w/w hypromellose (Methocel™ K100M CR);

about 24% w/w microcrystalline cellulose;

about 13% w/w lactose monohydrate;

about 0.5% w/w silica colloidal anhydrous;

about 0.5% w/w magnesium stearate;

about 5% w/w Eudragit L30D55; and

about 1% w/w Plasacryl HTP20.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form comprising:

about 24% w/w Compound (I), or a pharmaceutically acceptable salt and/orsolvate thereof;

about 9% w/w hypromellose (Methocel™ K100LV CR);

about 23% w/w hypromellose (Methocel™ K100M CR);

about 24% w/w microcrystalline cellulose;

about 13% w/w lactose monohydrate;

about 0.5% w/w silica colloidal anhydrous;

about 1% w/w magnesium stearate;

about 5% w/w Eudragit L30D55; and

about 1% w/w Plasacryl HTP20.

In one aspect, the present disclosure provides a method of reducing arisk of QT prolongation when treating a subject with Compound (I), or apharmaceutically acceptable salt and/or solvate thereof, the methodcomprising oral administration to the subject of a gastro-resistant,controlled release dosage form described herein.

In one aspect, the present disclosure provides a method of treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, the method comprising an oral administration to the subject ofa gastro-resistant, controlled release dosage form described herein,wherein the subject has a diagnosis of the disorder, e.g.,schizophrenia.

In one aspect, the present disclosure provides a method of treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, the method comprising a once daily oral administration to thesubject of a gastro-resistant, controlled release dosage form describedherein, wherein the subject has a diagnosis of the disorder, e.g.,schizophrenia.

In one aspect, the present disclosure provides a method of treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, the method comprising an oral administration to the subject ofa gastro-resistant, controlled release dosage form described herein,wherein the subject has a diagnosis of, e.g., schizophrenia, wherein thesubject having a diagnosis of schizophrenia has a CYP2D6 EM genotype.

In one aspect, the present disclosure provides a method of treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, the method comprising a once daily oral administration to thesubject of a gastro-resistant, controlled release dosage form describedherein, wherein the subject has a diagnosis of, e.g., schizophrenia,wherein the subject having a diagnosis of schizophrenia has a CYP2D6 EMgenotype.

In one aspect, the present disclosure provides a method of treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, the method comprising an oral administration to the subject ofa gastro-resistant, controlled release dosage form described herein(e.g., including a low dose of Compound (I), such as about 4 mg, 5 mg, 6mg, 7 mg, 8 mg, or about 16 mg), wherein the subject has a diagnosis of,e.g., schizophrenia, wherein the subject having a diagnosis ofschizophrenia has a CYP2D6 IM or PM genotype.

In one aspect, the present disclosure provides a method of treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, the method comprising a once daily oral administration to thesubject of a gastro-resistant, controlled release dosage form describedherein (e.g., including a low dose of Compound (I), such as about 4 mg,5 mg, 6 mg, 7 mg, 8 mg, or about 16 mg), wherein the subject has adiagnosis of, e.g., schizophrenia, wherein the subject having adiagnosis of schizophrenia has a CYP2D6 IM or PM genotype.

In one aspect, for any of the methods disclosed herein, the subject isin fed state prior to oral administration of the gastro-resistant,controlled release dosage form described herein.

In one aspect, for any of the methods disclosed herein, the subject isin fasted state prior to oral administration of the gastro-resistant,controlled release dosage form described herein.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form disclosed herein for use in reducing arisk of QT prolongation.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form disclosed herein for use in treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, e.g., the subject has a diagnosis of schizophrenia.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form disclosed herein for use in treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, e.g., the subject has a diagnosis of schizophrenia, wherein thesubject having a diagnosis of schizophrenia has a CYP2D6 EM genotype.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form disclosed herein for use in treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, e.g., the subject has a diagnosis of schizophrenia, wherein thesubject having a diagnosis of schizophrenia has a CYP2D6 IM or PMgenotype and the dosage form has a low dose of Compound (I), e.g., about4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or about 16 mg.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form disclosed herein for use in reducing arisk of QT prolongation, wherein the gastro-resistant, controlledrelease dosage form is administered once daily.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form disclosed herein for use in treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, e.g., the subject has a diagnosis of schizophrenia, wherein thegastro-resistant, controlled release dosage form is administered oncedaily.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form disclosed herein for use in treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, e.g., the subject has a diagnosis of schizophrenia, wherein thesubject having a diagnosis of schizophrenia has a CYP2D6 EM genotype,wherein the gastro-resistant, controlled release dosage form isadministered once daily.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form disclosed herein for use in treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, e.g., the subject has a diagnosis of schizophrenia, wherein thesubject having a diagnosis of schizophrenia has a CYP2D6 IM or PMgenotype and the dosage form has a low dose of Compound (I), e.g., about4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or about 16 mg, wherein thegastro-resistant, controlled release dosage form is administered oncedaily

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form disclosed herein for use in treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, e.g., the subject has a diagnosis of schizophrenia, wherein thesubject is in fed state prior to oral administration of the dosage form.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form disclosed herein for use in treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, e.g., the subject has a diagnosis of schizophrenia, wherein thesubject is in fasted state prior to oral administration of the dosageform.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form disclosed herein for use in treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, e.g., the subject has a diagnosis of schizophrenia, wherein thesubject having a diagnosis of schizophrenia has a CYP2D6 EM genotype,wherein the subject is in fed state prior to oral administration of thedosage form.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form disclosed herein for use in treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, e.g., the subject has a diagnosis of schizophrenia, wherein thesubject having a diagnosis of schizophrenia has a CYP2D6 EM genotype,wherein the subject is in fasted state prior to oral administration ofthe dosage form

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form disclosed herein for use in treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, e.g., the subject has a diagnosis of schizophrenia, wherein thesubject having a diagnosis of schizophrenia has a CYP2D6 IM or PMgenotype and the dosage form has a low dose of Compound (I), e.g., about4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or about 16 mg, wherein the subject is infed state prior to oral administration of the dosage form.

In one aspect, the present disclosure provides a gastro-resistant,controlled release dosage form disclosed herein for use in treating adisorder (e.g., negative symptoms of schizophrenia) in a subject in needthereof, e.g., the subject has a diagnosis of schizophrenia, wherein thesubject having a diagnosis of schizophrenia has a CYP2D6 IM or PMgenotype and the dosage form has a low dose of Compound (I), e.g., about4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or about 16 mg, wherein the subject is infasted state prior to oral administration of the dosage form.

In one aspect, the present disclosure provides for a use of agastro-resistant, controlled release dosage form disclosed herein in themanufacture of medicament for reducing a risk of QT prolongation.

In one aspect, the present disclosure provides for a use of agastro-resistant, controlled release dosage form disclosed herein in themanufacture of medicament for the treatment of a disorder (e.g.,negative symptoms of schizophrenia) in a subject in need thereof, e.g.,the subject has a diagnosis of schizophrenia.

In one aspect, the present disclosure provides for a use of agastro-resistant, controlled release dosage form disclosed herein in themanufacture of medicament for the treatment of a disorder (e.g.,negative symptoms of schizophrenia) in a subject in need thereof, e.g.,the subject has a diagnosis of schizophrenia, wherein the subject havinga diagnosis of schizophrenia has a CYP2D6 EM genotype.

In one aspect, the present disclosure provides for a use of agastro-resistant, controlled release dosage form disclosed herein in themanufacture of medicament for the treatment of a disorder (e.g.,negative symptoms of schizophrenia) in a subject in need thereof, e.g.,the subject has a diagnosis of schizophrenia, wherein the subject havinga diagnosis of schizophrenia has a CYP2D6 IM or PM genotype and thedosage form has a low dose of Compound (I), e.g., about 4 mg, 5 mg, 6mg, 7 mg, or about 8 mg.

In one aspect, the present disclosure provides for a use of agastro-resistant, controlled release dosage form disclosed herein in themanufacture of medicament for reducing a risk of QT prolongation,wherein the gastro-resistant, controlled release dosage form isadministered once daily.

In one aspect, the present disclosure provides for a use of agastro-resistant, controlled release dosage form disclosed herein in themanufacture of medicament for the treatment of a disorder (e.g.,negative symptoms of schizophrenia) in a subject in need thereof, e.g.,the subject has a diagnosis of schizophrenia, wherein thegastro-resistant, controlled release dosage form is administered oncedaily.

In one aspect, the present disclosure provides for a use of agastro-resistant, controlled release dosage form disclosed herein in themanufacture of medicament for the treatment of a disorder (e.g.,negative symptoms of schizophrenia) in a subject in need thereof, e.g.,the subject has a diagnosis of schizophrenia, wherein the subject havinga diagnosis of schizophrenia has a CYP2D6 EM genotype, wherein thegastro-resistant, controlled release dosage form is administered oncedaily.

In one aspect, the present disclosure provides for a use of agastro-resistant, controlled release dosage form disclosed herein in themanufacture of medicament for the treatment of a disorder (e.g.,negative symptoms of schizophrenia) in a subject in need thereof, e.g.,the subject has a diagnosis of schizophrenia, wherein the subject havinga diagnosis of schizophrenia has a CYP2D6 IM or PM genotype and thedosage form has a low dose of Compound (I), e.g., about 4 mg, 5 mg, 6mg, 7 mg, or about 8 mg, wherein the gastro-resistant, controlledrelease dosage form is administered once daily.

In one aspect, the present disclosure provides for a use of agastro-resistant, controlled release dosage form disclosed herein in themanufacture of medicament for the treatment of a disorder (e.g.,negative symptoms of schizophrenia) in a subject in need thereof, e.g.,the subject has a diagnosis of schizophrenia, wherein the subject is infasted state prior to oral administration of the dosage form.

In one aspect, the present disclosure provides for a use of agastro-resistant, controlled release dosage form disclosed herein in themanufacture of medicament for the treatment of a disorder (e.g.,negative symptoms of schizophrenia) in a subject in need thereof, e.g.,the subject has a diagnosis of schizophrenia, wherein the subject havinga diagnosis of schizophrenia has a CYP2D6 EM genotype, wherein thesubject is in fasted state prior to oral administration of the dosageform.

In one aspect, the present disclosure provides for a use of agastro-resistant, controlled release dosage form disclosed herein in themanufacture of medicament for the treatment of a disorder (e.g.,negative symptoms of schizophrenia) in a subject in need thereof, e.g.,the subject has a diagnosis of schizophrenia, wherein the subject havinga diagnosis of schizophrenia has a CYP2D6 IM or PM genotype and thedosage form has a low dose of Compound (I), e.g., about 4 mg, 5 mg, 6mg, 7 mg, or about 8 mg, wherein the subject is in fasted state prior tooral administration of the dosage form.

In one aspect, the present disclosure provides for a use of agastro-resistant, controlled release dosage form disclosed herein in themanufacture of medicament for the treatment of a disorder (e.g.,negative symptoms of schizophrenia) in a subject in need thereof, e.g.,the subject has a diagnosis of schizophrenia, wherein the subject is infed state prior to oral administration of the dosage form.

In one aspect, the present disclosure provides for a use of agastro-resistant, controlled release dosage form disclosed herein in themanufacture of medicament for the treatment of a disorder (e.g.,negative symptoms of schizophrenia) in a subject in need thereof, e.g.,the subject has a diagnosis of schizophrenia, wherein the subject havinga diagnosis of schizophrenia has a CYP2D6 EM genotype, wherein thesubject is in fed state prior to oral administration of the dosage form.

In one aspect, the present disclosure provides for a use of agastro-resistant, controlled release dosage form disclosed herein in themanufacture of medicament for the treatment of a disorder (e.g.,negative symptoms of schizophrenia) in a subject in need thereof, e.g.,the subject has a diagnosis of schizophrenia, wherein the subject havinga diagnosis of schizophrenia has a CYP2D6 IM or PM genotype and thedosage form has a low dose of Compound (I), e.g., about 4 mg, 5 mg, 6mg, 7 mg, or about 8 mg, wherein the subject is in fed state prior tooral administration of the dosage form.

Thus, in one aspect, the present disclosure provides a gastro-resistant,controlled release oral dosage form, which comprises (i) about 4 mg toabout 100 mg of Compound (I), or an equivalent amount of apharmaceutically acceptable salt and/or solvate thereof, and (ii) atleast one controlled release agent, wherein the dosage form produces,upon oral administration to a subject, a plasma pharmacokinetic (PK)profile for Compound (I) which comprises a T_(max) of between about 4and about 11 hours. In an embodiment, the T_(max) of Compound (I) in theplasma PK profile is between about 5 and about 10 hours; between about 6and about 9 hours, between about 7 and about 9 hours, or between about 6and about 8 hours.

In some embodiments, the amount of Compound (I) in the oral dosage formis 4 mg to 8 mg, 8 to 16 mg, 16 mg to 32 mg, 32 mg to 40 mg, 40 mg to 64mg, 64 mg to 80 mg, 80 mg to 100 mg or is about any of 4 mg, 8 mg, 16mg, 24 mg, 32 mg, 40 mg, 64 mg, 80 mg, 96 mg, or 100 mg.

In an embodiment, the dosage form comprises about 32 mg of Compound (I),or an equivalent amount of a pharmaceutically acceptable salt and/orsolvate thereof, and the plasma PK profile further comprises: (a) anAUC_(0-4 H) of less than about 68 h*ng/mL; (b) a C_(max) of Compound (I)of less than about 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21ng/mL, 22 ng/mL, or 23 ng/mL; and (c) an AUC_(0-24 hr) of between about75 h*ng/mL to about 350 h*ng/mL or between about 100 h*ng/mL to 300h*ng/mL. In an embodiment, the plasma PK profile for the BFB-520metabolite of Compound (I) comprises a C_(max) that is below 3.0 ng/mL,below 2.5 ng/mL, below 2.0 ng/mL, below 1.5 ng/mL or below 1.0 ng/mL.

In an embodiment, the dosage form comprises about 4 mg of Compound (I),or an equivalent amount of a pharmaceutically acceptable salt and/orsolvate thereof, and the plasma PK profile further comprises: (a) anAUC_(0-4 H) of less than about 8 h*ng/mL; (b) a C_(max) of Compound (I)of less than about 2.5 ng/mL; and (c) an AUC_(0-24 hr) of between about12 h*ng/mL to 35 h*ng/mL. In an embodiment, the plasma PK profile forthe BFB-520 metabolite of Compound (I) comprises a C_(max) that is below2.0 ng/mL, below 1.5 ng/mL, below 1.0 ng/mL, or below 0.5 ng/mL.

In an embodiment, the dosage form comprises about 8 mg of Compound (I),or an equivalent amount of a pharmaceutically acceptable salt and/orsolvate thereof, and the plasma PK profile further comprises: (a) anAUC_(0-4 H) of less than about 16 h*ng/mL; (b) a C_(max) of Compound (I)of less than about 5 ng/mL; and (c) an AUC_(0-24 hr) of between about 25h*ng/mL to 75 h*ng/mL. In an embodiment, the plasma PK profile for theBFB-520 metabolite of Compound (I) comprises a C_(max) that is below 2.5ng/mL, below 2.0 ng/mL, below 1.5 ng/mL, or below 1.0 ng/mL.

In an embodiment, the dosage form comprises about 16 mg of Compound (I),or an equivalent amount of a pharmaceutically acceptable salt and/orsolvate thereof, and the plasma PK profile further comprises: (a) anAUC_(0-4 H) of less than about 32 h*ng/mL; (b) a C_(max) of Compound (I)of less than about 10 ng/mL or less than about 6 ng/mL; and (c) anAUC_(0-24 hr) of between about 50 h*ng/mL to 150 h*ng/mL. In anembodiment, the plasma PK profile for the BFB-520 metabolite of Compound(I) comprises a C_(max) that is below 2.5 ng/mL, below 2.0 ng/mL, below1.5 ng/mL, or below 1.0 ng/mL.

In an embodiment, the dosage form comprises about 40 mg of Compound (I),or an equivalent amount of a pharmaceutically acceptable salt and/orsolvate thereof, and the plasma PK profile further comprises: (a) anAUC_(0-4 H) of less than about 80 h*ng/mL; (b) a C_(max) of Compound (I)of less than about 24 ng/mL or less than about 20 ng/mL; and (c) anAUC_(0-24 hr) of between about 125 h*ng/mL to 375 h*ng/mL. In anembodiment, the plasma PK profile for the BFB-520 metabolite of Compound(I) comprises a C_(max) that is below 3.5 ng/mL, below 3.0 ng/mL, below2.5 ng/mL, or below 2.0 ng/mL.

In an embodiment, the dosage form comprises about 64 mg of Compound (I),or an equivalent amount of a pharmaceutically acceptable salt and/orsolvate thereof, and the plasma PK profile further comprises: (a) anAUC_(0-4 H) of less than about 50, 60, 70, 80, 90, 100, 110, 120, or 130h*ng/mL; (b) a C_(max) of Compound (I) of less than about 36 ng/mL orless than about 25 ng/mL; and (c) an AUC_(0-24 hr) of between about 200h*ng/mL to 600 h*ng/mL. In an embodiment, the plasma PK profile for theBFB-520 metabolite of Compound (I) comprises a C_(max) that is below 4.0ng/mL, below 3.5 ng/mL, below 3.0 ng/mL, or below 2.5 ng/mL.

In an embodiment, the dosage form comprises about 80 mg of Compound (I),or an equivalent amount of a pharmaceutically acceptable salt and/orsolvate thereof, and the plasma PK profile further comprises: (a) anAUC_(0-4 H) of less than about 160 h*ng/mL; (b) a C_(max) of Compound(I) of less than about 48 ng/mL or less than about 40 ng/mL; and (c) anAUC_(0-24 hr) of between about 250 h*ng/mL to 750 h*ng/mL. In anembodiment, the plasma PK profile for the BFB-520 metabolite of Compound(I) comprises a C_(max) that is below 4.5 ng/mL, below 4.0 ng/mL, below3.5 ng/mL, or below 3.0 ng/mL.

In an embodiment, the dosage form comprises about 100 mg of Compound(I), or an equivalent amount of a pharmaceutically acceptable saltand/or solvate thereof, and the plasma PK profile further comprises: (a)an AUC_(0-4 H) of less than about 220 h*ng/mL; (b) a C_(max) of Compound(I) of less than about 72 ng/mL; and (c) an AUC_(0-24 hr) of betweenabout 325 h*ng/mL to 975 h*ng/mL. In an embodiment, the plasma PKprofile for the BFB-520 metabolite of Compound (I) comprises a C_(max)that is below 5.0 ng/mL, below 4.5 ng/mL, below 4.0 ng/mL, or below 3.5ng/mL.

In some embodiments of any of the above dosage forms, the plasma PKparameters are values determined after two once daily administrations ofa single unit of the dosage form. In an embodiment, the PK parameter isdetermined after the 3^(rd) or 4^(th) administration.

In an embodiment, the dosage form comprises about 32 mg of Compound (I)and, when administered to a subject, produces a plasma pharmacokinetic(PK) profile for Compound (I) which is similar to the target profileshown in FIG. 1.

In some embodiments of any of the above dosage forms, the plasma PKprofile for one or both of Compound (I) and the metabolite BFB-520 isproduced after the 1^(st), 2^(nd), 3^(rd), or 4^(th) once dailyadministration of a single unit of the dosage form.

In some embodiments, the plasma PK profile for one or both of Compound(I) and the metabolite BFB-520 is produced when administered to asubject in the fasted state. In other embodiments, the plasma PK profilefor one or both of Compound (I) and the metabolite BFB-520 is producedwhen administered to a subject in the fed state.

In an embodiment, a controlled release dosage form of the disclosurecomprises about 4 to about 100 mg of Compound (I) and produces a targetin vitro dissolution profile using a 24-hour, two-stage in vitrodissolution method which comprises a 2-hour acid stage and a 22-hourbuffer stage. The target in vitro dissolution profile comprises (a) nodetectable release of Compound (I) during the first 2.0 hours of thedissolution method and (b) release of at least 80% of the total amountof Compound (I) in the dosage form over a time period of 16-19 hours. Inan embodiment, the target in vitro dissolution profile comprises releaseof at least 85%, 90% or 95% of the amount of Compound (I) in the dosageform by hour 24 of the dissolution method.

In an embodiment, the target in vitro dissolution profile furthercomprises release of Compound (I) at a release rate that produces eachof the following cumulative percentages of the starting total amount:

(i) less than 0.6% by 2.5 hours;

(ii) from 0.2 to 7.9% by 3.0 hours;

(iii) from 2.5 to 19.2% by 4 hours;

(iv) from 12.7 to 34.0% by 6 hours;

(v) from 22.8 to 44.3% by 8 hours;

(vi) from 35.5 to 75.7% by 13 hours;

(vii) from 43.3 to 89.0% by 16 hours; and

(viii) from 59.3 to 96.9% by 19 hours.

In an embodiment, the target in vitro dissolution profile furthercomprises release of Compound (I) at a release rate that produces eachof the following cumulative percentages of the starting total amount:

(i) less than about 0.5% by 2.5 hours;

(ii) from about 2.8 to about 3.1% by 3.0 hours;

(iii) from about 9.0 to about 11.0% by 4 hours;

(iv) from about 14.5 to about 18.0% by 5 hours;

(v) from about 19.5 to about 24.5% by 6 hours;

(vi) from about 30.5 to about 38.0% by 8 hours;

(vii) from about 41.5 to about 51.0% by 10 hours;

(viii) from about 54.5 to about 67.0% by 13 hours;

(ix) from about 58.5 to about 71.5% by 14 hours;

(x) from about 61.5 to about 75.5% by 15 hours;

(xi) from about 70.0 to about 86.0% by 18 hours; and

(xii) from about 77.5 to about 95.0% by 21 hours.

In an embodiment, the CR dosage form comprises 32 mg of Compound (I) andgenerates in vitro cumulative dissolution and dissolution rate profilesthat are substantially similar to the target profile shown in FIG. 1 orto the target profile shown in Tables 6 and 7 in the Examples below.

In an embodiment, the target in vitro dissolution profile furthercomprises release of Compound (I) at a release rate that produces eachof the following cumulative percentages of the starting total amount:

(xiii) less than about 0.5% by 2 hours;

(xiv) from about 19 to about 29% by 4 hours;

(xv) from about 54 to about 64% by 8 hours; and

(xvi) from about 83 to about 93% by 16 hours.

In an embodiment, the target in vitro dissolution profile furthercomprises release of Compound (I) at a release rate that produces eachof the following cumulative percentages of the starting total amount:

(xvii) less than about 0.5% by 2 hours;

(xviii) about 24.1% by 4 hours;

(xix) about 59.2% by 8 hours; and

(xx) about 88.6% by 16 hours.

In each of the above embodiments, the dissolution method is preferablyconducted according to the dissolution method described in the Examplesbelow.

In an embodiment, the CR oral dosage form is a tablet which comprises acore tablet and an enteric coating. The core tablet comprises a desiredamount of Compound (I), a controlled release agent, a filler, a glidantand a lubricant and the enteric coating comprises at least one polymericcontrolled release agent with a dissolution property of greater than pH5.5, and an anti-tacking agent. In an embodiment, the enteric coatingdissolves at a pH greater than 6.0 or 6.5.

In an embodiment, the CR oral dosage form is a tablet which comprises acore tablet and an enteric coating. The core tablet comprises a desiredamount of Compound (I) or a pharmaceutically acceptable salt and/orsolvate thereof (e.g., MIN-101), a controlled release agent, a filler, aglidant and a lubricant and the enteric coating comprises at least onepolymeric controlled release agent with a dissolution property ofgreater than pH 5.5, and an anti-tacking agent. In an embodiment, theenteric coating dissolves at a pH greater than 6.0 or 6.5.

In some embodiments, the controlled release agent in the core tabletcomprises a mixture of (i) a low viscosity hypromellose with a viscosityof between about 15 millipascal-seconds (mPa·s) to about 100 mPa·s and(ii) a high viscosity hypromellose with a viscosity of about 100,000mPa·s, wherein each of the low and high viscosity hypromelloses is acontrolled release or sustained-release grade and is furthercharacterized by a methoxy content of 19.0% to 24.0% and ahydroxypropoxy content of 4.0% to 12.0%. In an embodiment, the highviscosity hypromellose is characterized by a methoxy content of 22.0% to24.0% and a hydroxypropoxy content of 9.5% to 11.5%. In an embodiment,the low viscosity hypromellose comprises about 10% of the weight of thecore tablet and the high viscosity hypromellose comprises about 24% ofthe weight of the core tablet.

In an embodiment, the core tablet comprises 38.4 mg of1H-Isoindol-1-one,2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-,hydrochloride, hydrate (1:1:2) and the controlled release agent in thecore table consists essentially of (i) 9.45% w/w of a hypromellosehaving the chemical and physical characteristics of the hypromelloseproduct marketed as METOLOSE® 90 SH 100 SR by Shin-Etsu Chemical Co.,Ltd., or METHOCEL™ K100LV CR; and (ii) 22.67% w/w of a hypromellosehaving the chemical and physical characteristics of the hypromelloseproduct marketed as METHOCEL™ K100M CR by The Dow Chemical Company.

In an embodiment, the dosage form further comprises a controlled releasecoating located between the core tablet and the enteric coating. Thecontrolled release coating comprises at least one controlled releasereagent. In an embodiment, the controlled release coating comprises asemipermeable membrane which comprises ethylcellulose as the controlledrelease agent.

In an embodiment of the dosage form that comprises a controlled releasecoating, the core tablet comprises 38.4 mg of 1H-Isoindol-1-one,2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-,hydrochloride, hydrate (1:1:2) and the controlled release agent in thecore table consists essentially of 9.36% w/w of a hypromellose havingthe chemical and physical characteristics of the hypromellose productmarketed as METHOCEL™ K15M CR by The Dow Chemical Company, or METHOCEL™K100LV CR; and 22.46% of a hypromellose having the chemical and physicalcharacteristics of the hypromellose product marketed as METHOCEL™ K100MCR by The Dow Chemical Company and the controlled release agent in thecontrolled release coating consists essentially of 0.94% w/w of anethylcellulose having the chemical and physical characteristics of theethylcellulose product marketed as Surelease® E-7-19040 by Colorcon.

In some embodiments of any of the above dosage forms, the entericcoating consists essentially of a mixture of (i) 4.68% w/w of acopolymer of methacrylic acid and ethyl acrylate having the samephysical and chemical properties as the copolymer marketed as EUDRAGIT®L 30 D-55 by Evonik Industries AG and (ii) 0.80% w/w of an anti-tackingagent having the chemical and physical characteristics of theanti-tacking product marketed as PlasACRYL™ by Evonik Industries AG.

In an embodiment, the gastro-resistant CR tablet of the disclosure has around shape, an oval shape, a capsule shape or an oblong shape. In anembodiment, the tablet is round, with a diameter of 10 mm and acurvature radius (R) of 10.

In other aspects, the present disclosure provides a batch compositionand a process for manufacturing a gastro-resistant CR oral dosage formdescribed herein.

In yet another aspect, the present disclosure provides a method ofreducing a risk of QT prolongation when treating a subject with Compound(I), the method comprising administering to the subject agastro-resistant CR oral dosage form described herein.

In a still further aspect, the present disclosure provides a method oftreating a disorder (e.g., negative symptoms of schizophrenia) in asubject in need thereof, the method comprising a once dailyadministration to the patient of a gastro-resistant CR oral dosage formdescribed herein. In one embodiment, the subject, e.g., a patient, has adiagnosis of schizophrenia. In an embodiment, the patient has adiagnosis of schizophrenia, a CYP2D6 extensive metabolizer (EM) genotypeand the oral dosage form comprises 32 mg to 64 mg of Compound (I). Inanother embodiment, the patient has a diagnosis of schizophrenia, aCYP2D6 poor metabolizer (PM) genotype and the gastro-resistant CR oraldosage form comprises 4 mg to 16 mg of Compound (I). In anotherembodiment, the patient has a diagnosis of schizophrenia, a CYP2D6intermediate metabolizer (IM) genotype and the gastro-resistant CR oraldosage form comprises 8 mg to 32 mg of Compound (I).

In another aspect, the present disclosure provides a gastro-resistant CRoral dosage form described herein for use in treating negative symptomsin a patient. In an embodiment, the patient has a diagnosis ofschizophrenia. In an embodiment, the dosage form is intended for use inimproving one or both of negative symptoms and cognitive impairment inpatients with a diagnosis of schizophrenia.

In another aspect, the present disclosure provides the use of agastro-resistant CR oral dosage form described herein for thepreparation of a medicament for treating negative symptoms in a patient.In an embodiment, the patient has a diagnosis of schizophrenia.

In another aspect, the present disclosure provides a kit for use intreating negative symptoms in a patient, the kit comprising agastro-resistant CR oral dosage form described herein and instructionsfor use of the dosage form. In an embodiment, the instructions includeinstructions for testing the patient to determine the patient's CYP2D6genotype. In an embodiment, the instructions include instructions foradministrating the dosage form to the patient in a fed state or in afasted state.

In all of the above aspects and embodiments of the invention, Compound(I) may be provided in the gastro-resistant CR oral dosage form as1H-Isoindol-1-one,2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-,hydrochloride, hydrate (1:1:2).

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

In the Drawings, various graphs are shown which include the plasmaconcentrations time profile of various compounds, including, forexample, 1H-Isoindol-1-one,2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-,i.e., Compound (I). In these Drawings, the use of the “MIN-101” or“MIN101” is intended to refer to the free base, i.e., Compound (I).

The foregoing summary, as well as the following detailed description ofthe disclosure, will be better understood when read in conjunction withthe appended drawings.

FIG. 1 shows an exemplary target plasma PK profile for Compound (I)produced by oral administration of a gastro-resistant, controlledrelease dosage form comprising 32 mg of Compound (I) (“Prediction newformulation”) compared to the observed plasma PK profile for Compound(I) produced by a previous 32 mg modified release MIN-101 tablet(described in Example 1) (“MR 32 mg”). The time profile is through 24hours.

FIG. 2 compares target in vitro dissolution profiles for Compound (I)(Target, red curve) with observed dissolution profiles for two exemplarygastro-resistant CR 32 mg tablets of the present disclosure, with theupper graph showing cumulative dissolution profiles and the lower graphshowing dissolution rate profiles. The time profile is through 24 hours.

FIG. 3 shows another exemplary target plasma PK profile for Compound (I)produced by oral administration of a gastro-resistant, controlledrelease dosage form comprising 32 mg of Compound (I) to a subject ineither the fed state or fasted state (“Optimal formulation”) compared tothe observed plasma PK profiles for Compound (I) produced by a previous32 mg modified release MIN-101 tablet (described in Example 1) inpatients in the fasted state or fed state. The time profile is through24 hours.

FIG. 4 is a graph of Compound (I) plasma concentrations time profile forsubjects administered a MR 32 mg tablet. The time profile is through 36hours.

FIG. 5 is a graph of Compound (I) plasma concentrations time profile forsubjects administered a GR-01 tablet. The time profile is through 36hours.

FIG. 6 is a graph of Compound (I) plasma concentrations time profile forsubjects administered a GR-02 tablet. The time profile is through 36hours.

FIG. 7 is a graph of mean Compound (I) plasma concentrations timeprofile for subjects administered MR 32 mg tablets, GR-01 tablets, orGR-02 tablets. The time profile is through 48 hours.

FIG. 8 is a graph of the rates of increase or decrease in Compound (I)plasma concentrations time profile for subjects administered MR 32 mgtablets, GR-01 tablets, or GR-02 tablets. The time profile is through 8hours.

FIG. 9 is a graph of BFB-520 plasma concentrations time profile forsubjects administered a MR 32 mg tablet. The time profile is through 36hours.

FIG. 10 is a graph of BFB-520 plasma concentrations time profile forsubjects administered a GR-01 tablet. The time profile is through 36hours.

FIG. 11 is a graph of BFB-520 plasma concentrations time profile forsubjects administered a GR-02 tablet. The time profile is through 36hours.

FIG. 12 is a graph of mean BFB-520 plasma concentrations time profilefor subjects administered MR 32 mg tablets, GR-01 tablets, or GR-02tablets. The time profile is through 48 hours.

FIG. 13 is a graph of the rates of increase or decrease in BFB-520plasma concentrations time profile for subjects administered MR 32 mgtablets, GR-01 tablets, or GR-02 tablets. The time profile is through 8hours.

FIG. 14 is a pair of graphs of predicted Compound (I) steady stateplasma concentrations time profile for subjects administered 4 dailydoses of a MR 32 mg tablet or a GR-01 tablet (32 mg) based on actualdata observed following Day 1 dosing. The time profile is through 96hours.

FIG. 15 is a pair of graphs of predicted BFB-520 steady state plasmaconcentrations time profile for subjects administered 4 daily doses of aMR 32 mg tablet or a GR-01 tablet (32 mg) based on actual data observedfollowing Day 1 dosing. The time profile is through 96 hours.

FIG. 16 is a pair of graphs of predicted Compound (I) steady stateplasma concentrations time profile for subjects administered 4 daily 64mg (2×32 mg) doses of a MR 32 mg tablet or a GR-01 tablet. The timeprofile is through 96 hours.

FIG. 17 is a pair of graphs of predicted BFB-520 steady state plasmaconcentrations time profile for subjects administered 4 daily 64 mg(2×32 mg) doses of a MR 32 mg tablet or a GR-01 tablet. The time profileis through 96 hours.

FIG. 18 is a pair of graphs of predicted Compound (I) steady stateplasma concentrations time profile for subjects administered 4 dailydoses of a MR 32 mg tablet or a GR-02 tablet (32 mg) based on actualdata observed following Day 1 dosing. The time profile is through 96hours.

FIG. 19 is a pair of graphs of predicted BFB-520 steady state plasmaconcentrations time profile for subjects administered 4 daily doses of aMR 32 mg tablet or a GR-02 tablet (32 mg) based on actual data observedfollowing Day 1 dosing. The time profile is through 96 hours.

FIG. 20 is a pair of graphs of predicted Compound (I) steady stateplasma concentrations time profile for subjects administered 4 dailydoses of a MR 32 mg tablet or a GR-02 tablet based on actual dataobserved following Day 1 dosing. The time profile is through 96 hours.

FIG. 21 is a pair of graphs of predicted BFB-520 steady state plasmaconcentrations time profile for subjects administered 4 daily 64 mg(2×32 mg) doses of a MR 32 mg tablet or a GR-02 tablet. The time profileis through 96 hours.

FIG. 22 is a graph of Compound (I) plasma concentrations time profilefor subjects administered GR-01 tablets in fed state. The time profileis through 36 hours.

FIG. 23 is a graph of Compound (I) plasma concentrations time profilefor subjects administered GR-01 tablets in fasted state. The timeprofile is through 36 hours.

FIG. 24 is graph comparing mean Compound (I) plasma concentrations timeprofile for subjects administered GR-01 tablets in fed or fasted state.The time profile is through 48 hours.

FIG. 25 is a graph of BFB-520 plasma concentrations time profile forsubjects administered GR-01 tablets in fed state. The time profile isthrough 48 hours.

FIG. 26 is a graph of BFB-520 plasma concentrations time profile forsubjects administered GR-01 tablets in fasted state. The time profile isthrough 48 hours.

FIG. 27 is graph comparing mean BFB-520 plasma concentrations timeprofile for subjects administered GR-01 tablets in fed or fasted state.The time profile is through 48 hours.

FIG. 28 is a pair of graphs of predicted Compound (I) steady stateplasma concentrations time profile for subjects administered 4 dailydoses of a GR-01 tablet (32 mg) based on actual data observed followingDay 1 dosing in fed or fasted state. The time profile is through 96hours.

FIG. 29 is a pair of graphs of predicted BFB-520 steady state plasmaconcentrations time profile for subjects administered 4 daily doses of aGR-01 tablet (32 mg) based on actual data observed following Day 1dosing in fed or fasted state. The time profile is through 96 hours.

FIG. 30 is a pair of graphs of predicted Compound (I) steady stateplasma concentrations time profile for subjects administered 4 daily 64mg (2×32 mg) doses of a GR-01 tablet in fed or fasted state. The timeprofile is through 96 hours.

FIG. 31 is a pair of graphs of predicted BFB-520 steady state plasmaconcentrations time profile for subjects administered 4 daily 64 mg(2×32 mg) doses of a GR-01 tablet (64 mg) in fed or fasted state. Thetime profile is through 96 hours.

DETAILED DESCRIPTION

The present disclosure relates to novel gastro-resistant CR oral dosageforms comprising Compound (I) or a pharmaceutically acceptable saltand/or solvate thereof, bulk compositions and processes formanufacturing the dosage forms, and use of the dosage forms fortherapeutic treatment of patients suffering from various disorders andconditions.

In one embodiment, the present disclosure relates to novelgastro-resistant CR oral dosage forms comprising Compound (I), or apharmaceutically acceptable salt and/or solvate thereof, wherein uponoral administration to a subject, the C_(max) of Compound (I) and itsmetabolite, BFB-520, are reduced while the AUC_((0-tau)) is maintainedcompared to previously disclosed formulations and/or dosage forms, e.g.,those as disclosed in U.S. Pat. No. 9,458,130.

In one embodiment, the present disclosure relates to novelgastro-resistant CR oral dosage forms comprising Compound (I), or apharmaceutically acceptable salt and/or solvate thereof, wherein uponoral administration to a subject, similar AUC-based exposure of Compound(I) is maintained compared to a previous study with previously disclosedformulations and/or dosage forms, e.g., those as disclosed in U.S. Pat.No. 9,458,130, which achieved its primary endpoint of improving negativesymptoms in patients with schizophrenia with both doses tested, 64 mgand 32 mg.

In one embodiment, the present disclosure relates to novelgastro-resistant CR oral dosage forms comprising Compound (I) or apharmaceutically acceptable salt and/or solvate thereof, wherein uponoral administration to a subject, the t_(1/2) of Compound (I) isprolonged compared to previously disclosed formulations and/or dosageforms, e.g., those as disclosed in U.S. Pat. No. 9,458,130.

In one embodiment, the present disclosure relates to novelgastro-resistant CR oral dosage forms comprising Compound (I) or apharmaceutically acceptable salt and/or solvate thereof, wherein uponoral administration to a subject, the C_(max) of BFB-520 in thesubject's plasma is reduced to promote drug safety.

In one embodiment, the present disclosure relates to novelgastro-resistant CR oral dosage forms comprising Compound (I) or apharmaceutically acceptable salt and/or solvate thereof, wherein uponoral administration to a subject, the C_(max) of BFB-520 is reduced byabout 30% or more (e.g., 30%, 35%, or 40%) compared to previouslydisclosed formulations and/or dosage forms, e.g., those as disclosed inU.S. Pat. No. 9,458,130.

In one embodiment, the reduction of the C_(max) of BFB-520 in thesubject leads to a reduction in the potential for transient QTcincreases observed in a previous study at the higher dose but not at thelower dose. In one example, administration of novel gastro-resistant CRoral dosage forms described herein comprising Compound (I), or apharmaceutically acceptable salt and/or solvate thereof, does not resultin an observable QTc prolongations.

In one embodiment, the present disclosure relates to novelgastro-resistant CR oral dosage forms comprising Compound (I) or apharmaceutically acceptable salt and/or solvate thereof, wherein theadministration of the dosage form does not result in an observable foodeffect, i.e., the administration of the dosage form may occur with orwithout food without changing its pharmacokinetic properties.

In one embodiment, the present disclosure relates to novelgastro-resistant CR oral dosage forms comprising Compound (I) or apharmaceutically acceptable salt and/or solvate thereof, wherein thedosage forms comprising Compound (I) retain previously establishedoverall safety and tolerability profiles.

The novel gastro-resistant CR oral dosage forms disclosed herein allowfor the delivery of Compound (I) to a lower part of the gastrointestinaltract, which unexpectedly reduced the highest concentration of BFB-520.This unexpected pharmacokinetic effect resulted in no observable QTcprolongations in the subjects who were administered these novelgastro-resistant CR oral dosage forms.

Definitions and Abbreviations

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Notwithstandingthe foregoing, and except where stated otherwise, the followingdefinitions apply throughout the specification and claims.

Chemical names, common names, and chemical structures may be usedinterchangeably to describe the same structure. If a chemical compoundis referred to using both a chemical structure and a chemical name andan ambiguity exists between the structure and the name, the structure isunderstood to predominate.

All references to Compound (I) herein include all pharmaceuticallyacceptable salts (such as MIN-101) and/or all solvates (e.g., includinghydrates) and alternative physical forms thereof unless otherwiseindicated. All doses recited herein are based on the molecular weight ofthe free base Compound (I), which is 366.43 g/mole, rather than themolecular weight of the pharmaceutically acceptable salt or solvate(e.g., hydrate) thereof or any excipients in the composition, unlessotherwise indicated.

All amounts of a component of an oral dosage form described herein thatare indicated based on % w/w refer to the total weight of the oraldosage form, unless otherwise indicated.

The term “about” as part of a quantitative expression such as “about X”,includes any value that is 10% higher or lower than X, and also includesany numerical value that falls between X−10% and X+10%. Thus, forexample, a weight of about 40 g includes a weight of between 36 to 44 g.

“Administration” refers to introducing an agent, such as a compound ordosage form described herein, into a subject. The related terms“administering” and “administration of” (and grammatical equivalents)refer both to direct administration, which may be administration to asubject by a medical professional or by self-administration by thesubject, and/or to indirect administration, which may be the act ofprescribing a drug such as a dosage form described herein. For example,a physician who instructs a patient to self-administer a drug and/orprovides a patient with a prescription for a drug is administering thedrug to the patient.

“BFB-520” is a metabolite of Compound (I) and has the structure shown inFormula II below:

“BFB-999” is a metabolite of Compound (I) and the structure of a maleatesalt of BFB-999 shown in Formula III below:

“Similar PK profile” as used herein with respect to a plasmaconcentration time profile produced by oral administration to a subjectof a dosage form of the disclosure is a plasma concentration timeprofile that is substantially similar to the target profile shown inFIG. 1 such that a first dosage form comprising Compound (I) thatproduces the target plasma concentration time profile in FIG. 1 and asecond dosage form comprising Compound (I) that produces the similarplasma concentration time profile would result in a PK property, such asAUC, considered to be bioequivalent by a regulatory agency. In anembodiment, the regulatory agency is the U.S. Food and DrugAdministration.

“BNSS” is the Brief Negative Symptom Scale.

“Comprising” or “comprises” as applied to a particular dosage form,composition, method or process described or claimed herein means thatthe dosage form, composition or method includes all of the recitedelements in a specific description or claim, but does not exclude otherelements. “Consists essentially of” and “consisting essentially of”means that the described or claimed composition, dosage form, method orprocess does not exclude other materials or steps that do not materiallyaffect the recited physical, pharmacological, pharmacokinetic propertiesor therapeutic effects of the composition, dosage form, method orprocess. “Consists of” and “consisting of” means the exclusion of morethan trace elements of other ingredients and substantial method orprocess steps.

“Controlled release” or “CR” as used herein with respect to an oraldosage form of the disclosure means that Compound (I) is released fromthe dosage form according to a pre-determined profile that may includewhen and where release occurs after oral administration and/or aspecified rate of release over a specified time period.

“Controlled release agent” as used herein with respect to an oral dosageform of the disclosure refers to one or more substances or materialsthat modulate release of Compound (I) from the dosage form. Controlledrelease agents may be materials which are organic or inorganic,naturally occurring or synthetic, such as polymeric materials,triglycerides, derivatives of triglycerides, fatty acids and salts offatty acids, talc, boric acid and colloidal silica.

“CYP2D6 allele” refers to one of over 100 named versions of the CYP2D6gene that are present in the general population, and typicallyclassified into one of three categories: active (functional); decreasedactivity (partially active or decreased function) and inactive(non-functional).

Active CYP2D6 alleles include: *1, *2, *2A, *33, *35, *39, *48, and *53.

Decreased activity CYP2D6 alleles include: *9, *10, *17, *29, *41, *49,*50, *54, *55, *59, *69, and *72.

Inactive CYP2D6 alleles include: *3, *4, *5 (deletion), *6, *7, *8, *11,*12, *13, *14A, *14B, *15, *18, *19, *20, *21, *38, *40, *42, *44, *56,*56A, *56B, and *68.

“CYP2D6 Extensive Metabolizer (EM) genotype” as applied to a subjectmeans the subject has a CYP2D6 which results in CYP2D6 metabolicactivity considered as normal. CYP2D6 EM genotypes include combinationsof: (a) two active CYP2D6 alleles, (b) one active and one decreasedactivity CYP2D6 allele, and (c) one active and one inactive CYP2D6allele.

“CYP2D6 Intermediate Metabolizer (IM) genotype” as applied to a subjectmeans the subject has a CYP2D6 genotype, which results in reduced CYP2D6metabolic activity. CYP2D6 IM genotypes include combinations of: (a) oneinactive and one decreased activity CYP2D6 allele; and (c) two decreasedactivity CYP2D6 alleles.

“CYP2D6 PM genotype” as applied to a subject means the subject has apositive test result for a CYP2D6 poor metabolizer genotype and thuslikely to have no CYP2D6 activity. A CYP2D6 PM genotype is 2 inactivealleles.

“CYP2D6 UM genotype” as applied to a subject means the subject has apositive test result for a CYP2D6 ultrarapid metabolizer genotype andthus likely to have higher than average CYP2D6 activity. A CYP2D6 UMgenotype is 3 or more active alleles.

“Enteric coating” as used herein with respect to a dosage form of thedisclosure refers to a pH-dependent material that surrounds a corecomprising Compound (I) and which remains substantially intact in theacid environment of the stomach, but which dissolves in the pHenvironment of the intestines.

In one embodiment, in the dosage forms of the disclosure the filler isselected from the group consisting of microcrystalline cellulose,lactose monohydrate, sucrose, glucose, and sorbitol.

“Glidant” as used herein refers to a substance used to promote powderflow by reducing interparticle cohesion. In one embodiment, in thedosage forms of the disclosure the glidant is selected from the groupconsisting of silica colloidal anhydrous, starch, and talc.

“Lubricant” as used herein refers to a substance that preventsingredients from sticking and/or clumping together in the machines usedin preparation of the dosage forms of the disclosure. In one embodiment,in the dosage forms of the disclosure the lubricant is selected from thegroup consisting of magnesium strearate, steric acid, and vegetablestearin.

“Fasted condition” or “fasted state” as used to describe a subject meansthe subject has not eaten for at least 4 hours before a time point ofinterest, such as the time of administering a dosage form describedherein. In an embodiment, a subject in the fasted state has not eatenfor at least any of 6, 8, 10 or 12 hours prior to administration of adosage form described herein.

“Fed condition” or “fed state” as used to describe a subject hereinmeans the subject has eaten less than 4 hours before a time point ofinterest, such as the time of administering a dosage form describedherein. In an embodiment, a subject in the fed state has not eaten forat least any of 3, 2, 1 or 0.5 hours prior to administration of a dosageform described herein.

“Gastro-resistant” or “GR” as applied to a CR oral dosage form describedherein means that release of Compound (I) in the stomach of a subjectshall not exceed 5%, 2.5%, 1% or 0.5% of the total amount of Compound(I) in the dosage form.

“MIN-101” is a code name for 1H-Isoindol-1-one,2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-,hydrochloride, hydrate (1:1:2), with an alternative name of2-{1-[2-(4-Fluorophenyl)-2-oxoethyl]piperidin-4-ylmethyl}-2,3-dihydroisoindol-1-onehydrochloride dihydrate.

“Oral dosage form” as used herein refers to a pharmaceutical drugproduct that contains a specified amount (dose) of Compound (I) as theactive ingredient, or a pharmaceutically acceptable salt and/or solvatethereof, and inactive components (excipients), formulated into aparticular configuration that is suitable for oral administration, suchas a tablet or capsule.

“Pharmaceutically acceptable salt” as used herein with respect toCompound (I), means a salt form of Compound (I) as well as hydrates ofthe salt form with one or more water molecules present. Such salt andhydrated forms retain the biological activity of Compound (I) and arenot biologically or otherwise undesirable, i.e., exhibit minimal, ifany, toxicological effects. In an embodiment, the pharmaceuticallyacceptable salt of Compound (I) has a single HCl molecule and two watermolecules, i.e., 1H-Isoindol-1-one,2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-,hydrochloride, hydrate (1:1:2).

“PANSS” is Positive and Negative Syndrome Scale.

“Pharmacokinetic parameter” means a measurement or characteristic thatdescribes the pharmacokinetic properties of a compound of interest. PKparameters used herein are defined below.

“AUC” is total area under the plasma concentration-time curve, which isa measure of exposure to a compound of interest, and is the integral ofthe concentration-time curve after a single dose or at steady state. AUCis expressed in units of ng·H/mL (ng×H/mL).

“AUC_((0-4 H))” means the AUC from 0 hours to 4 hours afteradministration of a single dose.

“AUC_((0-24 H))” means the AUC from 0 hours to 24 hours afteradministration of a single dose.

“AUC_(last)” means the AUC from time 0 to the last quantifiableconcentration (C_(last)).

“AUC_((0-tau))” means the AUC from 0 hours to the end of a dosinginterval.

“C_(max)” means the observed maximum (peak) plasma concentration of aspecified compound, such as Compound (I), after administration of a doseof a composition comprising the compound. In an embodiment, the C_(max)is measured after 2 or more doses of the composition. In an embodiment,the C_(max) is measured when the specified compound reachessteady-state.

“C_(min)” means the observed minimum plasma concentration of a specifiedcompound, such as Compound (I), after administration of a dose of acomposition comprising the compound. In an embodiment, the C_(max) ismeasured after 2 or more doses of the composition. In an embodiment, theC_(max) is measured when the specified compound reaches steady-state.

“C_(ss)” means the concentration at the steady state.

“C_(ave)” means the average concentration which is the AUC over timeratio.

“C_(p)” means the plasma concentration of a specified compound, such asCompound (I), at any time T after administration of a dose of acomposition comprising the compound.

“C_(p(last))” means the last measured C_(p), with reference to the timeof collection of the last of a series of blood samples for assay for thespecified compound.

“C_(p(T))” means the C_(p) at the specified time; thus C_(p(4 H)) andC_(p(12 H)) are the C_(p) at 4 hours and 24 hours, respectively.

“H” means hours.

“PK” is pharmacokinetic(s).

“Steady-state” means the rate of absorption of a specified compound ofinterest such as Compound (I) is equal to the rate of elimination of thecompound.

“Tau” means a dosing interval (H). For example, for once daily dosing,tau is 24 H,

T_(max) means the time to maximum (or peak) plasma or serumconcentration of a specified therapeutic compound after administrationof a single dose of a composition comprising the compound and beforeadministration of a second dose.

V_(max) means the maximum absorption rate (mg/H).

“Subject” and “patient” may be used interchangeably herein, and refer toa human of any age.

“Therapeutically effective amount”, as used herein with respect totherapeutic uses of a dosage form comprising Compound (I) orpharmaceutically salt and/or solvate thereof, means an amount of thefree base (Compound (I)) that is sufficient to treat, ameliorate, orprevent a specified disease, disease symptom, disorder or condition, orto exhibit a detectable therapeutic or inhibitory effect. The effect canbe detected by any assay method known in the art. The effective amountfor a particular subject may depend upon the subject's body weight,size, and health; the nature and extent of the condition; and whetheradditional therapeutics are to be administered to the subject.Therapeutically effective amounts for a given situation can bedetermined by routine experimentation that is within the skill andjudgment of the clinician.

“Treat”, “treating”, “treatment” and similar terms, as used herein withrespect to one or more specified disease symptoms shall include themanagement and care of a patient for the purpose of improving one ormore of the specified symptoms, and include administration of agastro-resistant, controlled release oral dosage form described hereinat a dosing frequency and for a treatment period that are sufficient toprevent the onset of one or more of the symptoms, reduce the frequency,intensity or severity of one or more of the symptoms, delay or avoid thedevelopment of additional symptoms, or any combination of thesetreatment objectives. In an embodiment, the effect of treatment with adosage form of the present disclosure is assessed by comparing theseverity of the subject's symptoms at baseline (e.g., prior totreatment) and after at least one treatment period. In an embodiment,the treatment period is at least one week, at least two weeks, at leastfour weeks, at least six weeks, at least eight weeks, at least 10 weeksor at least twelve weeks or more. In an embodiment, the symptoms to betreated is at least one negative symptom in a schizophrenic ornon-schizophrenic patient, the dosage form comprises 32 mg of Compound(I), the dosing frequency is once daily, and the treatment period is atleast eight weeks.

Summary of Gastro-Resistant Controlled Release (CR) Oral Dosage Forms

In one embodiment, the present disclosure relates to a gastro-resistant,CR oral dosage form comprising between about 4 mg to about 100 mg ofCompound (I) or an equivalent amount of a pharmaceutically acceptablesalt and/or solvate of Compound (I), wherein the gastro-resistant, CRoral dosage form is selected from the group consisting of a 32 mg CRGR-01 tablet, 32 mg CR GR-02 tablet, a 32 mg CR GR-01/B tablet, a 64 mgCR GR-01/B tablet, a 32 mg CR GR-01/C tablet, and a 64 mg CR GR-01/Ctablet.

In one embodiment, the 32 mg CR GR-01 tablet has the followingcomposition:

CR GR-01 tablet Composition % w/w mg/tablet Function MIN-101¹ 12.0938.40 Active ingredient Hypromellose 9.45 30.00 Controlled release(Metolose ® 90SH 100 SR) excipient Hypromellose 22.67 72.00 Controlledrelease (Methocel ™ K100M CR) excipient Microcrystalline Cellulose 29.9595.10 Filler Lactose Monohydrate 18.89 60.00 Filler Silica ColloidalAnhydrous 0.47 1.50 Glidant Magnesium stearate 0.94 3.00 Lubricant Total(Core Tablet) 94.47 300.00 Eudragit L30D55 4.72 15.00 Controlled releaseexcipient Plasacryl HTP20 0.80 2.55 Anti-tacking agent Total 100.00317.55 ¹Salt correction factor of 1.2 applied NA: Not Applicable

In one embodiment, the 32 mg CR GR-02 tablet has the followingcomposition:

CR GR-02 tablet Composition % w/w mg/tablet Function MIN-101¹ 11.9838.40 Active ingredient Hypromellose 9.36 30.00 Controlled release(Methocel ™ K15M CR) excipient Hypromellose 22.46 72.00 Controlledrelease (Methocel ™ K100M CR) excipient Microcrystalline Cellulose 29.6795.10 Filler Lactose Monohydrate 18.72 60.00 Filler Silica ColloidalAnhydrous 0.47 1.50 Glidant Magnesium stearate 0.94 3.00 Lubricant Total(Core Tablet) 93.59 300.00 Eudragit L30D55 4.68 15.00 Controlled releaseexcipient Plasacryl HTP20 0.80 2.55 Anti-tacking agent SureleaseE-7-19040 0.94 3.00 Controlled release excipient Total 100.00 320.55¹Salt correction factor of 1.2 applied NA: Not Applicable

In one embodiment, the 32 mg CR GR-01/B tablet has the followingcomposition:

GR-01/B-32 mg Component/Ingredient mg/tablet % (w/w) MIN-101¹ 38.4012.11 Hypromellose 30.00 9.45 (METHOCEL ™ K100LV CR) Hypromellose 72.0022.67 (Methocel ™ K100M CR) Microcrystalline Cellulose 96.60 30.42Lactose 60.00 18.89 Silica Colloidal Anhydrous 1.50 0.47 Magnesiumstearate 1.50 0.47 Eudragit L30D55 15.0 4.72 Plasacryl HTP20 2.55 0.80Total 317.55 100.00 ¹Salt correction factor of 1.2 applied

In one embodiment, the 32 mg CR GR-01/C tablet has the followingcomposition:

GR-01/C-32 mg Component/Ingredient mg/tablet % (w/w) MIN-101¹ 38.4012.11 Hypromellose 30.00 9.45 (METHOCEL ™ K100LV CR) Hypromellose 72.0022.67 (Methocel ™ K100M CR) Microcrystalline Cellulose 95.10 29.95Lactose 60.00 18.89 Silica Colloidal Anhydrous 1.50 0.47 Magnesiumstearate 3.00 0.94 Eudragit L30D55 15.0 4.72 Plasacryl HTP20 2.55 0.80Total 317.55 100.00

In one embodiment, the 64 mg CR GR-01/B tablet has the followingcomposition:

GR-01/B-64 mg Component/Ingredient mg/tablet % (w/w) MIN-101¹ 76.8 24.19Hypromellose 30.00 9.45 (METHOCEL ™ K100LV CR) Hypromellose 72.00 22.67(Methocel ™ K100M CR) Microcrystalline Cellulose 77.40 24.37 Lactose40.80 12.85 Silica Colloidal Anhydrous 1.50 0.47 Magnesium stearate 1.500.47 Eudragit L30D55 15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55100.00 ¹Salt correction factor of 1.2 applied

In one embodiment, the 64 mg CR GR-01/C tablet has the followingcomposition:

GR-01/C-64 mg Component/Ingredient mg/tablet % (w/w) MIN-101¹ 76.8 24.19Hypromellose 30.00 9.45 (METHOCEL ™ K100LV CR) Hypromellose 72.00 22.67(Methocel ™ K100M CR) Microcrystalline Cellulose 75.90 23.91 Lactose40.80 12.85 Silica Colloidal Anhydrous 1.50 0.47 Magnesium stearate 3.000.94 Eudragit L30D55 15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55100.00Design and Manufacture of Gastro-Resistant Controlled Release OralDosage Forms

An object of the present disclosure is to provide a gastro-resistant,controlled release oral dosage form comprising between about 4 mg toabout 100 mg of Compound (I) or an equivalent amount of apharmaceutically acceptable salt and/or solvate of Compound (I). Thedosage form is formulated to exhibit, upon oral administration to asubject, a specific, desired release profile for Compound (I) whichreduces the maximum plasma concentrations of BFB-520 while providing atherapeutically effective amount of Compound (I) during one or moredosing intervals. This desired release profile is achieved in two ways:(a) delay release of Compound (I) until after gastric emptying pushesthe dosage form to the small intestine and then (b) provide sustainedrelease of at least about 90%, 95% or 100% of the amount of Compound (I)in the dosage form at a rate that provides a plasma PK profile whichcomprises a T_(max) for Compound (I) of between about 4 and about 22hours.

This in vivo release profile for Compound (I) is designed to reduce thesubject's plasma levels of BFB-520 below a threshold that is correlatedwith a greater risk for QT prolongation. In an embodiment, the thresholdis a C_(max) for BFB-520 that is below 5.0 ng/mL, below 4.5 ng/mL, below4.0 ng/mL, below 3.5 ng/mL, below 3.0 ng/mL, below 2.5 ng/mL, below 2.0ng/mL, below 1.5 ng/mL, below 1.0 ng/mL, or below 0.5 ng/mL.

In some embodiments, the plasma PK profile for Compound (I) is furthercharacterized in terms of one or more additional PK parameters, such asC_(max), AUC_((0-tau)), C_(min) and other PK parameters defined above.It will be understood by the skilled person that the values for some ofthese additional PK parameters will depend, at least in part, on theamount of Compound (I) in the dosage form.

The values for the T_(max) and other plasma PK parameters produced by adosage form described herein may exhibit some inter-individual variationwithin a population of subjects. Thus, in some embodiments, certainplasma PK parameters are expressed as mean values determined for apopulation of at least 2, 4, 8, 16 or more subjects. In an embodiment,the population consists of healthy volunteers. In an embodiment, eachsubject in the population has a positive test for an EM genotype. In anembodiment, each subject in the population has a positive test for an EMgenotype or an IM genotype. In an embodiment, each subject in thepopulation has a positive test for an IM genotype or a PM genotype. Inan embodiment, each subject in the population has a positive test for aPM genotype.

Compound (I) may be synthesized using standard synthetic methods andprocedures for the preparation of organic molecules and functional grouptransformations and manipulations, including the use of protectivegroups, as can be obtained from the relevant scientific literature orfrom standard reference textbooks in the field. Although not limited toany one or several sources, recognized reference textbooks of organicsynthesis include: Smith, M. B.; March, J. March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 5^(th) ed.; John Wiley& Sons: New York, 2001; and Greene, T. W.; Wuts, P. G. M. ProtectiveGroups in Organic Synthesis, 3^(rd); John Wiley & Sons: New York, 1999.A method for preparing Compound (I) is described in U.S. Pat. No.7,166,617, the contents of which are incorporated herein in theirentirety.

In an embodiment, the drug substance form of Compound (I) used in thedosage form is a dihydrate of a hydrochloride salt of Compound (I),which has the chemical name 1H-Isoindol-1-one,2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-,hydrochloride, hydrate (1:1:2), which has a molecular formula ofC₂₂H₂₃FN₂O₂, HCl, 2H₂O and a molecular weight of 438.92. Methods forpreparing this Compound (I) drug substance are described in U.S. Pat.Nos. 7,166,617 and 9,458,130. An amount of this drug substance that isequivalent to a specified amount of free base may be calculated bymultiplying the specified amount of Compound (I) by 1.2; thus, 38.4 mgof this drug substance is equivalent to 32.0 mg of Compound (I).

In an embodiment, the delayed and sustained-release properties of the CRoral dosage form may be provided by encasing a sustained-releasecomposition comprising the desired amount of Compound (I), or apharmaceutically acceptable salt and/or solvate thereof, within anenteric coating.

Various physical and chemical approaches for designing sustained-releasecompositions are well known in the art. Any sustained-releasecomposition that is capable of releasing Compound (I) to provide the invivo plasma PK profile described herein may be used to prepare a dosageform of the disclosure. In an embodiment, the sustained-releasecomposition comprises at least one polymeric material that modulatesrelease of Compound (I). Suitable polymeric materials include, but arenot limited to, cross-linked polyvinylpyrrolidone,hydroxypropylmethylcellulose, hydroxypropylcellulose, cross-linkedsodium carboxymethylcellulose, carboxymethyl starch, starch andderivatives thereof, acrylic and methacrylic acid polymers andcopolymers, polyesters, polyanhydrides, polymethylvinylether/anhydridecopolymers, potassium methacrylate-divinylbenzene copolymers,polyvinylalcohols, glucan, scleroglucan, mannan, betacyclodextrins andcyclodextrin derivatives containing linear and/or branched polymericchains. In one embodiment, the polymeric material is ahydroxyproplymethocellulose.

In an embodiment, a mixture of a low viscosity and a high viscosityhypromellose is used as the controlled release agent in thesustained-release composition. The viscosity properties of suitablehypromelloses may be determined in a 2% by weight solution in water at20° C. as described in USP Hypromellose Monograph, Official Dec. 1,2016, which is available athttp://www.usp.org/usp-nf/official-text/stage-6/hypromellose-2015-11-20.

The enteric coating, which typically comprises a pH-sensitive polymer,begins to dissolve in an aqueous solution at pH greater than 5.5, and inone embodiment, begins to dissolve in an aqueous solution at pH greaterthan 6.0. In one embodiment, the pH-sensitive polymer begins to dissolvein an aqueous solution at pH greater than 6.5. In one embodiment, thepH-sensitive polymer begins to dissolve in an aqueous solution at pH6.7. In an embodiment, the amounts of Compound (I) released in thestomach from a gastro-resistant CR dosage form administered to subjectsin a fed state or a fasted state are about the same (e.g., less than 5%,less than 2% or less than 1% difference).

The composition and thickness of the enteric coating are typicallychosen to substantially maintain its integrity in the stomach, whileallowing substantially all of the enteric coating to dissolve after thedosage form leaves the stomach. In an embodiment, substantially all ofthe enteric coating dissolves within 15 minutes, 30 minutes, 1 hour or 2hours after the dosage form leaves the stomach.

The design and preparation of gastro-resistant enteric coatings arewell-known in the formulation art. Polyacids having an appropriate pKarange may be used to prepare enteric coatings. Non-limiting examples ofsuitable enteric coating materials are polymerized gelatin, shellac,methacrylic acid copolymer type C NF, cellulose butyrate phthalate,cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinylacetate phthalate (PVAP), cellulose acetate phthalate (CAP), celluloseacetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulosesuccinate, carboxymethyl ethylcellulose (CMEC), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and acrylic acid polymersand copolymers, typically formed from methyl acrylate, ethyl acrylate,methyl methacrylate and/or ethyl methacrylate with copolymers of acrylicand methacrylic acid esters. For example, the enteric coating maycomprise a copolymer based on methacrylic acid and ethyl acrylatemarketed as EUDRAGIT® L 30 D-55 by Evonik Industries AG. In anembodiment, the coating comprises a mixture of (i) EUDRAGIT® L 30 D-55at 4.5% to 5.0%, w/w, or about 4.7% w/w and (ii) PlasACRYL™ HTP20 at0.80% w/w.

In another aspect, the disclosure provides a batch composition andprocess for manufacturing a gastro-resistant CR oral dosage formdescribed herein. In an embodiment, a batch composition formanufacturing a 32 mg-dosage form comprises the components listed inTable 4 in Example 4 below. In another embodiment, a batch compositionfor manufacturing a 32 mg-dosage form comprises the components listed inTable 5 in Example 4 below. or Table in Example 4 below. Examples ofprocesses that are suitable for manufacturing these 32-mg dosage formsare described in flowcharts 1 and 2 of Example 4.

Analytical Methods

A. In Vitro Dissolution Testing

To assess the potential for a proposed gastro-resistant CR oral dosageform comprising Compound (I) to produce the desired in in vivo releaseprofile and plasma PK provide for Compound (I), in vitro dissolutiontesting as described in the Examples below may be performed.

In an embodiment, the dosage form comprises 32 mg and producescumulative dissolution and dissolution rate profiles that aresubstantially similar to the target profile, the CR-GR-01 profile or theCR-GR-02 profile shown in FIG. 1 and in Tables 6 and 7 below. In anembodiment, the cumulative dissolution amount and dissolution rate ateach time point in substantially similar profiles are within +/−10% ofthe values for the corresponding time point in the target, CR-GR-01 orCR-GR-02 dissolution profiles shown in Tables 6 and 7.

B. Detection of Compound (I) and BFB-520 in Human Plasma

To assess whether a gastro-resistant CR oral dosage form comprisingCompound (I) produces the desired PK profile for one or both of Compound(I) and BFB-520, plasma concentrations of the compound(s) of interestmay be determined at various time points after administration of thedosage form to a single subject, but is typically determined in a groupof two or more subjects. In an embodiment, PK profile is determined in agroup of at least 8, 12, 16 or 20 subjects. In an embodiment, the groupcomprises healthy male and female subjects. In an embodiment, the numberof subjects in the group is chosen to allow a statistically significantassessment of whether the PK profile produced by a test oral dosage formis a bioequivalent PK profile with respect to the PK profile shown inFIG. 1.

An open-label, randomized, 3-treatment sequence, 3-period study toevaluate the PK profile of Compound (I) and its metabolite BFB-520 aftersingle oral administration of 3 formulations of MIN-101 (2 prototypes ofCR gastro-resistant (GR) formulations (GR-01 and GR-02) and 1 comparatorMR formulation (MR32)) is summarized in Scheme 1 (MIN-101) and Scheme 2(BFB-520). Full details of these experiments are found in the Examplessection.

Scheme 1. Summary of MIN-101 PK Study for MR32, GR-01, and GR-02Formulations. MR32 MIN101 DATA AND PARAMETERS (from n = 12 subjectscross-over) CMAX 29.52 ng/ml AUC 291.55 H · ng/ml TMax 2.4 H GR01 MIN101RELATVIE BIOAVAILABILITY VERSUS MR32 (from n= 12 subjects cross-over)CMAX 19.59 ng/ml F = 69.9% AUC 284.5 H · ng/ml F = 101.3% TMax 6.0 HGR02 MIN101 RELATIVE BIOAVAILABILITY VERSUS MR32 (from n = 13 subjectscross-over) CMAX 15.43 ng/ml F = 54.33% AUC 253.01 H · ng/ml F = 86.9%TMax 15.2 H PLASMA CONCENTRATIONS RATE OF MIN101 INCREASE (VMax) MR32GR01 GR02 VMax ng/ml/H 26.2 11.9 2.9 RATIO Test/MR32 REF 0.45 0.4

Scheme 2. Summary of BFB-520 PK Study for MR32, GR-01, and GR-02Formulations. MR32 BFB-520 DATA AND PARAMETERS (from n = 12 subjectscross-over) CMAX 1.91 ng/ml AUC 30.26 H · ng/ml TMax 6.9 H GR01 BFB-520RELATIVE BIOAVAILABILITY VERSUS MR32 (from n = 12 subjects cross-over)CMAX 1.43 ng/ml F = 80.48% AUC 27.48 H · ng/ml F = 96.l % TMax 12.5 HGR02 BFB-520 RELATIVE BIOAVAILABILTIY VERSUS MR32 (from n = 12 subjectscross-over) CMAX 1.27 ng/ml F = 69.48% AUC 27.53 H · ng/ml F = 88.46%TMax 17.5 H PLASMA CONCENTRATIONS RATE OF BFB-520 INCREASE (VMax) MR32GR01 GR02 VMax ng/ml/H 0.84 0.54 0.2 RATIO Test/MR32 REF 0.64 0.24

The PK profiles of MIN-101 and its metabolite BFB-520 were predicted for3 formulations of MIN-101 (2 prototypes of CR gastro-resistant (GR)formulations (GR-01 and GR-02) and 1 comparator MR formulation (MR32))at 2 doses. (32 mg and 64 mg), based on 4 daily dosings. These studiesare summarized in Scheme 3 (32 mg) and Scheme 4 (64 mg). Full detailsare found in the Examples section.

Scheme 3. Summary of Predicted Plasma Concentrations of MIN-101 andBFB-520 for MR32, GR-01, and GR-02 Formulations (32 mg). PREDICTED 32 mgMR32 GR01 AND GR02 PLASMA CONCENTRATIONS AT DAY 4 MR32 GR01 GR01 GR02GR02 MIN101 CMaxSS 27.1 20.9 ng/ml F = 76.9% 15.4 ng/ml F = 56.7%AUCSS72-96 292.6 287.6 H · ng/ml F = 98.3% 248.3 H · ng/ml F = 84.9%CMinSS 3.32 ng/ml 7.17 ng/ml BFB-520CMaxSS 1.89 1.46 ng/ml F = 77.2%1.23 ng/ml F = 64.8% AUCSS72-96 29.1 26.3 H · ng/ml F = 90.6% 23.6 H ·ng/ml F = 81.4% CMinSS 0.5 0.66 ng/ml 0.79 ng/ml

Scheme 4. Summary of Predicted Plasma Concentrations of MIN-101 andBFB-520 for MR32, GR-01, and GR-02 Formulations (64 mg). PREDICTED 64 mgMR32 GR01 AND GR02 PLASMA CONCENTRATIONS AT DAY 4 2xMR32 2xGR01 2xGR012xGR02 2xGR02 MIN101 CMaxSS 54.28 41.77 ng/ml F = 76.9% 30.77 ng/ml F =56.7% AUCSS72-96 585.2 577.6 H · ng/ml F = 98.7% 498.6 ng/ml F = 85.2%CMinSS 6.64 12.93 ng/ml 14.35 ng/ml BFB-520 CMaxSS 3.79  2.92 ng/ml F =77.2%  2.45 ng/ml F = 64.8% AUCSS72-96 58.1  52.8 H · ng/ml F = 90.8% 47.4 H · ng/ml F = 81.6% CMinSS 0.99  1.32 ng/ml  1.58 ng/ml

The PK profiles of the GR-01 formulation in healthy CYP2D6 EM male andfemale subjects in fed and fasted states are summarized in Scheme 5(MIN-101) and Scheme 6 (BFB-520). Subjects who completed part 1 of thestudy (evaluation of the PK profile of MIN-101 and its metaboliteBFB-520 in the GR-01, GR-02, and MR32 formulations) returned andreceived a further single oral dose of GR-01 under fed or fastedconditions to allow the assessment of food effect by comparison of thePK properties to those obtained in part 1 (Examples 9-12). There was awash-out period of 14±2 days after part 1. Full details of theseexperiments are found in the Examples section.

Scheme 5. Summary of MIN-101 PK Study for GR-01 Formulation in Fed andFasted States. GR01 FED MIN101 (from n = 12 subjects cross-over) CMAX20.89 ng/ml F = 108.97% versus FASTED AUC 269.19 H · ng/ml F = 95.14%versus FASTED TMax 12.5 H GR01 FASTED MIN101 (from n = 12 subjectscross-over) CMAX 19.59 ng/ml AUC 284.52 H · ng/ml TMax 6.0 H

Scheme 6. Summary of BFB-520 PK Study for GR-01 Formulation in Fed andFasted States. GR01 FED BFB-520 (from n = 12 subjects cross-over) CMAX1.69 ng/ml F = 121.32% versus FASTED AUC 30.12 H · ng/ml F = 111.58%versus FASTED TMax 18.25 H GR01 FASTED BFB-520 (from n = 12 subjectscross-over) CMAX 1.43 ng/ml AUC 27.48 H · ng/ml TMax 12.5 H

The PK profiles of MIN-101 and its metabolite BFB-520 were predicted inthe fed and fasted states for gastro-resistant formulation GR-01 at 2doses (32 mg and 64 mg), based on 4 daily dosings. These studies aresummarized in Scheme 7 (32 mg) and Scheme 8 (64 mg), respectively. Fulldetails are found in the Examples section.

Scheme 7. Summary of Predicted Plasma Concentrations of MIN-101 andBFB-520 for GR-01 (32 mg) in the Fed and Fasted States. PREDICTED 32 mgGR01 FED AND FASTED PLASMA CONCENTRATIONS AT DAY 4 GR01 FED GR01 FASTEDMIN101 CMaxSS 16.7 F = 80.0% 20.9 ng/ml AUCSS72-96 263.8 F = 91.7% 287.6H · ng/ml CMinSS 3.32 6.46 ng/ml BFB-520 CMaxSS 1.51 F = 103.7% 1.46ng/ml AUCSS72-96 29.5 F = 109.4% 26.3 H · ng/ml CMinSS 1.03 0.66 ng/ml

Scheme 8. Summary of Predicted Plasma Concentrations of MIN-101 andBFB-520 for GR-01 (64 mg) in the Fed and Fasted States. PREDICTED 64 mgGR01 FED AND FASTED PLASMA CONCENTRATIONS AT DAY 4 GR01 FED GR01 FASTEDMIN101 CMaxSS 33.41 F = 80.0% 41.77 ng/ml AUCSS72-96 527.5 F = 91.3%577.6 H · ng/ml CMinSS 16.17 12.93 ng/ml BFB-520 CMaxSS 3.01 F = 103.7%2.91 ng/ml AUCSS72-96 59.0 F = 109.1% 54 H · ng/ml CMinSS 2.06 1.32ng/ml

BFB-520 is believed to be metabolized in part by CYP2D6. In clinicalstudies of MIN-101, CYP2D6 poor metabolizers have exhibited high plasmalevels of BFB-520. Thus, in an embodiment, the C_(max) for BFB-520 isassessed after oral administration of a test dosage form comprisingCompound (I) to only subjects who have been assigned an IM CYP2D6genotype or an EM CYP2D6 genotype using a commercially availablegenotype test. In an embodiment, all of the subjects have been assignedan EM CYP2D6 genotype.

Levels of Compound (I) and the metabolite BFB-520 produced in plasmaafter oral administration of an oral dosage form of the disclosure maybe determined by the method described below. It is expected thatvariations of and improvements to this method could be employed as well.

Blood samples from subjects are collected on sodium heparin tubes atvarious time points of interest. A suitable sampling schedule includesthe following:

-   -   Day 1 (D1): at pre-dose; 1 h; 2 h; 3 h; 4 h; 6 h; 8 h; 10 h; 12        h and 16 h;    -   Day 2 to Day 6 (D2-D6): at pre-dose    -   Day 7 (D7): at pre-dose; 1 h; 2 h; 3 h; 4 h; 6 h; 8 h; 10 h; 12        h; 16; 24 h (D8) and 48 h (D9).

After blood centrifugation, a desired number of aliquots (typically 2)of each plasma sample are prepared in suitable storage containers (e.g.,polypropylene tubes tightly capped to prevent leak and desiccation whichcould occur during storage). The containers containing the plasmasamples are stored at −80° C. for up to one month before analysis.

A GLP validated method to detect and quantify Compound (I) and itsmetabolites BFB-520 and BFB-999 employs liquid chromatographic (LC)analysis coupled to a mass spectrometry detection (MS/MS) after aliquid/liquid extraction step of Compound (I) and metabolites BFB-520and BFB-999 from plasma samples.

The analytical method uses two internal standards (a deuterated analogof MIN-101 (designated herein as [²H₆]-MIN-101 or MIN-101-d6 orCYR-101-d6) and BFB-784 for both BFB-520 and BFB-999), which weresubmitted to the same analytical procedure as MIN-101, BFB-520 andBFB-999 in plasma samples. MIN-101-d6 and BFB-784 have the structuresshown in Formulas IV and V below:

Chromatograms are processed by default in an automatic mode.Chromatographic peaks of MIN-101, BFB-520, BFB-999 and internalstandards (IS) are identified according to their retention times. Therecorded response is expressed as an area ratio of MIN-101 toMIN-101-d6, and of BFB-520 or BFB-999 to BFB-784.

The lower limit of quantification (LLOQ) of this analytical method inplasma is 0.25 ng/mL for MIN-101 and its metabolites BFB-520 andBFB-999.

Details of the analytical method are described in Example 7 below. It isexpected that variations of and improvements to this analytical methodcould be employed as well.

Treatment Methods

The gastro-resistant CR oral dosage forms of the present disclosure maybe useful for treating diseases or conditions that are susceptible totreatment with Compound (I). As not limiting examples, it is believedthat Compound (I) can potentially be used to treat schizophrenic andnon-schizophrenic patients with one or more of the following symptoms orconditions: negative symptoms, depressive symptoms, sleep disorders andcognitive impairment.

In a phase 2b study, MIN-101 at 32 mg and 64 mg doses, demonstratedrapid, statistically significant and clinically meaningful reductions innegative symptoms in patients with schizophrenia. The oral dosage formsused in this Phase 2b study were the 32 mg MR tablet described inExample 1 below and an essentially identical 64 mg MR tablet. Neither ofthese MR tablets had a GR coating and each produced in vitro dissolutionand plasma PK profiles that are different than those produced by thegastro-resistant CR oral dosage forms of the present disclosure.

Negative symptoms generally refer to a reduction in normal functioning,and include five major sub-domains: blunted affect (affectiveflattening, blunted expression), alogia (poverty of speech), amotivation(loss of volition), anhedonia (reduced ability to experience oranticipate pleasure) and asociality (social withdrawal). While negativesymptoms are a well-documented and intensively studied aspect ofschizophrenia, this class of symptoms has been identified in patientswith other psychiatric and neurological disorders, including, forexample, Alzheimer's disease and other dementias, particularlyfrontotemporal dementia (FTD), autism spectrum disorder (ASD), bipolardisorder (BPD), major depressive disorder (MDD), Parkinson's disease,temporal lobe epilepsy, stroke, and traumatic brain injury (TBI) (see,e.g., Boone et al, J. of Internat. Neuropsycol. Soc., 2003, Vol 9, pages698-709; Bastiaansen, J. et al., J. Autism Dev. Disord. 2011, Vol41:1256-1266; Getz, K. et al., Am. J. Psychiatry 2002, Vol 159:644-651;Winograd-Gurvich, C. et al., Brain Res. Bulletin, 2006, Vol. 70:312-321;Galynker et al., Neuropsychiatry Neuropsychol Behav Neurol 2000, Vol13:171-176; Galynker I, et al., J. Nerv. Ment. Dis 1997, Vol185:616-621; Chaudhury, S., et al., Indian J. of Neurotrauma 2005, Vol2:13-21; Ameen, S et al., German J. of Psychiatry 2007). Indeed, asearly as 2001, it was proposed that negative symptoms are common tomental illnesses generally (Herbener and Harrow, Schizophrenia Bulletin2001, Vol. 27:527-537). Furthermore, reports of several populationstudies have concluded that between 20-22% of the general populationhave one or more negative symptoms, and that the majority of subjectswith negative symptoms do not exhibit a clinical diagnosed psychiatricdisorder (Werbeloff, N. et al., PLoS ONE 2015, Vol 10:e0119852;Barrantes-Vidal, N., et al., Schizophr. Res. 2010, Vol 122:219-225).

Thus, it is an object of the present disclosure to treat at least onenegative symptom in a subject by a method of administering to thesubject a gastro-resistant CR dosage form described herein one time perday (QD). In an embodiment, the subject is diagnosed with schizophrenia.In another embodiment, the subject does not have a clinical diagnosis ofschizophrenia, i.e., is a non-schizophrenic patient.

For purposes of the disclosure encompassed herein, the term “negativesymptoms” is to be understood as including primary negative symptomstypically associated with schizophrenia, the negative symptoms measuredin the PANSS negative symptoms subscale score, the negative factor scorebased on the pentagonal structure model method, and the negativesymptoms measured in the BNSS.

In an embodiment, the negative symptom is one of the five majorsub-domains of negative symptoms: blunted affect, alogia, amotivation,anhedonia and asociality. The core characteristics of each sub-domainare described below.

Blunted affect (affective flattening, blunted expression) ischaracterized by reduced intensity and range of emotional expression asmanifested via vocal and non-verbal modes of communication includingintonation (prosody), facial expression, hand-gestures and bodymovements.

Alogia (poverty of speech) is characterized by decreased quantity ofspeech, reduced spontaneous speech and loss of conversational fluency.

Amotivation (loss of volition) is characterized by deficits in theinitiation and maintenance of goal-directed behaviors like work, study,sport, personal hygiene and daily tasks, especially when requiring andeffort (cognitive or physical) and significant organization, as well asdeficits in desire to undertake such activities. This sub-domain isrelated to apathy and lack of energy.

Anhedonia (reduced ability to experience or anticipate pleasure) ischaracterized by the looking forward to a reward, recreational or otherpleasurable experience (“wanting”) being more markedly and consistentlyimpaired (anticipatory anhedonia) than the appreciation (“liking”) ofthe experience itself (consummatory anhedonia).

Asociality (social withdrawal) is characterized by diminished interestin, motivation for, and appreciation of social interactions with others,like family and friends, loss of interest in intimate (sexual)relationships independent of any somatic problems, and for a child, mayinclude loss of interest in playing with other children.

In some embodiments, the dosage form is administered to the subject oncea day for a first treatment period of sufficient length to achieveimprovement in at least one negative symptom. In an embodiment, thefirst treatment period is at least 2 weeks, at least 4 weeks, at least 6weeks, at least 8 weeks, at least 10 weeks or at least 12 weeks. In anembodiment, positive symptoms in a subject treated with the dosage formare stable during the treatment period, i.e., remain at substantiallythe same level as at baseline. In an embodiment, the level ofimprovement in negative symptoms is a reduction of at least 3 points onthe PANSS five factor (pentagonal structure model) negative symptomfactor scores after 12 weeks of treatment. In an embodiment, thesubject's negative symptom score continues to improve from 12 weeks toat least about 24, 36 or 48 weeks of treatment. The PANSS pentagonalstructure model is described in WHITE L, HARVEY PD, OPLER L, LINDENMAYERJ. EMPIRICAL ASSESSMENT OF THE FACTORIAL STRUCTURE OF CLINICAL SYMPTOMSIN SCHIZOPHRENIA. PSYCHOPATHOLOGY. 1997; 30(5):263-74.

In some embodiments, if a subject experiences improvement in at leastone negative symptom during the first treatment period, thenadministration of the therapeutically effective dose of Compound (I) iscontinued for a second treatment period of at least 12 weeks, at least24 weeks, at least 48 weeks, or until the subject is determined toexhibit functional improvement subsequent to improvement in the negativesymptoms. In an embodiment, positive symptoms in a subject treated withthe dosage form are stable during at least part of the second treatmentperiod, i.e., remain at substantially the same level as at baseline.

In some embodiments, the subject has a diagnosis of schizophrenia. In anembodiment, a subject selected for treatment with an oral dosage form ofthe disclosure has a base-line PANSS negative sub-score greater than orequal to 20. In an embodiment, the selected subject also has baselinescores of less than 4 on the following PANSS items: excitement,hyperactivity, hostility, suspiciousness, uncooperativeness and poorimpulse control. In an embodiment, the selected schizophrenic subjecthas exhibited stable positive symptoms of schizophrenia for at least theprevious one, two or three months and has exhibited negative symptomsfor at least the previous one, two or three months.

In some embodiments, the schizophrenic subject treated with agastro-resistant, CR oral dosage form of the present disclosure hasprominent negative symptoms. In an embodiment, a schizophrenic subjectis defined as having prominent negative symptoms when the subject hashaving a score ≥4 (moderate) on at least three subscale items in thePANSS negative symptoms subscale items but not on PANSS positivesubscale items. In an embodiment, the subject has both prominentpositive and prominent negative symptoms when the subject has scores ≥4on items for both positive and negative symptom items.

Up to 75% of schizophrenic patients suffer from cognitive impairment,and the phase 2b study of MIN-101 discussed above showed improvement incognitive function. Thus, in an aspect, administration of agastro-resistant CR oral dosage form of the present disclosure to apatient with a diagnosis of schizophrenia is intended to improvecognitive function in the patient.

In some embodiments, the subject has not been previously treated with ananti-psychotic drug. In other embodiments, the subject has discontinuedprior treatment with an anti-psychotic drug due to experiencing one ormore of the following: satisfactory reduction in positive symptoms, aninadequate response for negative symptoms, or intolerable side effects.

A secondary outcome of the phase 2b study of MIN-101 discussed above waspatients' performance on the Calgary Depression Scale for Schizophrenia(CDSS) ADDINGTON D, ADDINGTON J, MATICKA-TYNDALE E. ASSESSING DEPRESSIONIN SCHIZOPHRENIA: THE CALGARY DEPRESSION SCALE. BRITISH JOURNAL OFPSYCHIATRY SUPPLEMENT 1993; (22):39-44. The CDSS has little overlap withpositive and negative symptoms and has become the recommended scale toassess the severity of depression in patients with schizophrenia. In thephase 2b study, the severity of symptoms as measured by the CDSS wasreduced following treatment with 32 or 64 mg of MIN-101 compared toplacebo. A correlation analysis between baseline treatment effects onnegative symptoms and on depression symptoms in this patient cohortdemonstrated there was only a small correlation between MIN-101'seffects on these two symptom categories. Thus, since the effects ofMIN-101 on negative symptoms and depression symptoms in schizophreniapatients were largely independent of each other, MIN-101 has thepotential to alleviate one or more depression symptoms in patients whoare not schizophrenic.

Thus, another object of the present disclosure is to treat at least onesymptom of depression in a subject in need thereof by a method ofadministering a gastro-resistant CR dosage form described herein. In anembodiment, the subject has a diagnosis of schizophrenia. In anembodiment, the improvement in depression symptoms in a schizophrenicpatient is measured using the CDSS.

It is another object of the present disclosure to reduce the risk for QTprolongation in a subject treated with Compound (I) by administering tothe subject Compound (I) as formulated in a gastro-resistant CR dosageform described herein. In an embodiment, the subject has been identifiedas having one or more risk factors for drug-induced QT prolongation. Inan embodiment, the subject discontinued previous treatment with acompound other than Compound (I) due to experiencing QT prolongation. Inan embodiment, the subject discontinued previous treatment with adifferent dosage form comprising Compound (I) due to experiencing QTprolongation. In an embodiment, the subject has a diagnosis selectedfrom the group consisting of: prominent negative symptoms ofschizophrenia, prominent positive and prominent negative symptoms ofschizophrenia, major depressive disorder (MDD), a sleep disorder andcognitive impairment.

In some embodiments of any of the above treatment methods, thegastro-resistant oral dosage form is administered in the morning orevening. In an embodiment, the dosage form is administered at least twohours before eating.

In some embodiments of any of the above treatment methods, the subjectis 12 or more years of age. In some embodiments, the subject is at least14, 16, 18, or 20 years old. In some embodiments, the subject is lessthan 50, 45, 40, 35 or 30 years old. In an embodiment, the subject is atleast 16 years old and less than any of 40, 35 or 30 years old.

In some embodiments of any of the above treatment methods, the dosageform may be administered to the subject in combination with anothertherapeutic agent. In an embodiment, the other therapeutic agent doesnot inhibit CYP2D6 activity. In an embodiment, the subject is diagnosedwith schizophrenia and the other therapeutic agent is an anti-psychoticdrug.

In some embodiments of any of the above treatment methods, the subjectmay have been assigned an IM genotype or and EM genotype. In anembodiment, the subject has been assigned an EM genotype.

In some embodiments of any of the above treatment methods, the oraldosage form may comprise 32 mg of Compound (I). In an embodiment, theoral dosage form consists essentially of the components listed in Table2 or Table 3 below.

Examples Example 1: Description of a 32 mg MR Tablet Used in the Phase2b Trial of MIN-101

The MR 32 mg tablets are supplied as round (diameter 10 mm and R=10)white-coated tablets free from visual defects. Each tablet contains 32mg of Compound (I). The complete statement of the components andquantitative composition of MR 32 mg tablet is given in Table 1 below.

TABLE 1 Composition of MR 32 mg tablet MR 32mg tablet Composition % w/wmg/tablet Function MIN-101¹ 12.19 38.40 Active ingredient Hypromellose9.52 30.00 Controlled (Methocel ™ K100LV CR) release excipientHypromellose 22.86 72.00 Controlled (Methocel ™ K4M CR) releaseexcipient Microcrystalline Cellulose 30.19 95.10 Filler (Avicel PH102)Lactose Monohydrate 19.05 60.00 Filler (Fast Flo 316) Silica ColloidalAnhydrous 0.48 1.50 Glidant (Aerosil 200 Pharma) Magnesium stearate 0.953.00 Lubricant (vegetable grade source Hyqual NF) Total (core tablets)95.23 300.00 Sepifilm (LP 770 Blanc) 4.76 15 Coating Agent Total 100.00315.00 ¹Salt correction factor of 1.2 applied NA: Not Applicable

Example 2: Description of an Exemplary 32 mg Gastro-Resistant CR Tablet

The CR GR-01 tablets are supplied as round (diameter 10 mm and R=10)tablets, free from visual defects. Each tablet contains 32 mg ofCompound (I). The complete statement of the components and quantitativecomposition of CR GR-01 tablet is given in Table 2.

TABLE 2 Composition of CR GR-01 tablet CR GR-01 tablet Composition % w/wmg/tablet Function MIN-101¹ 12.09 38.40 Active ingredient Hypromellose9.45 30.00 Controlled (Metolose ® 90SH 100 SR) release excipientHypromellose 22.67 72.00 Controlled (Methocel ™ K100M CR) releaseexcipient Microcrystalline Cellulose 29.95 95.10 Filler (Avicel PH102)Lactose Monohydrate 18.89 60.00 Filler (Fast Flo 316) Silica ColloidalAnhydrous 0.47 1.50 Glidant (Aerosil 200 Pharma) Magnesium stearate 0.943.00 Lubricant (vegetable grade source Hyqual NF) Total (Core Tablet)94.47 300.00 Eudragit L30D55 4.72 15.00 Controlled release excipientPlasacryl HTP20 0.80 2.55 Anti-tacking agent Total 100.00 317.55 ¹Saltcorrection factor of 1.2 applied NA: Not Applicable

Example 3: Description of Another Exemplary 32 mg Gastro-Resistant CRTablet

The CR GR-02 tablets are supplied as round (diameter 10 mm and R=10)tablets, free from visual defects. Each tablet contains 32 mg ofCompound (I). The complete statement of the components and quantitativecomposition of CR GR-02 tablet is given in Table 3 below.

TABLE 3 Composition of CR GR-02 tablet CR GR-02 tablet Composition % w/wmg/tablet Function MIN-101¹ 11.98 38.40 Active ingredient Hypromellose9.36 30.00 Controlled (Methocel ™ K15M CR) release excipientHypromellose 22.46 72.00 Controlled (Methocel ™ K100M CR) releaseexcipient Microcrystalline Cellulose 29.67 95.10 Filler (Avicel PH102)Lactose Monohydrate 18.72 60.00 Filler (Fast Flo 316) Silica ColloidalAnhydrous 0.47 1.50 Glidant (Aerosil 200 Pharma) Magnesium stearate 0.943.00 Lubricant (vegetable grade source Hyqual NF) Total (Core Tablet)93.59 300.00 Eudragit L30D55 4.68 15.00 Controlled release excipientPlasacryl HTP20 0.80 2.55 Anti-tacking agent Surelease E-7-19040 0.943.00 Controlled release excipient Total 100.00 320.55 ¹Salt correctionfactor of 1.2 applied NA: Not Applicable

Example 4: Batch Formula for CR GR-01 and CR GR-02 Tablets

A representative batch size for the CR GR-01 and CR GR-02 tablets are5,400 tablets. The batch formulas are described in Tables 4 and 5 below.

TABLE 4 Batch Formula for CR GR-01 tablet Composition kg/batch MIN-1010.206 Hypromellose Metolose ® 90SH 100SR 0.162 Hypromellose Methocel ™K100M CR 0.389 Microcrystalline Cellulose 0.514 Lactose 0.324 SilicaColloidal Anhydrous 0.008 Magnesium stearate 0.016 Eudragit L30D55 0.081Plasacryl HTP 20 0.014 Total 1.714 NA: Not Applicable

TABLE 5 Batch Formula for CR GR-02 tablet Composition kg/batch MIN-1010.207 Hypromellose Methocel ™ K15M CR 0.162 Hypromellose Methocel ™K100M CR 0.389 Microcrystalline Cellulose 0.514 Lactose 0.324 SilicaColloidal Anhydrous 0.008 Magnesium stearate 0.016 Eudragit L30D55 0.081Plasacryl HTP 20 0.014 Surelease E-7-19040 0.016 Total 1.731

TABLE 5A Batch Formula for GR-01/B Tablets (representative batch formulasize is 150 000 tablets Composition kg/batch MIN-101 5.75 HypromelloseMethocel ™ K100 LV CR 4.5 Hypromellose Methocel ™ K100M CR 10.80Microcrystalline Cellulose 14.5 Lactose 9 Silica Colloidal Anhydrous0.22 Magnesium stearate 0.22 Eudragit L30D55 2.25 Plasacryl HTP 20 0.380Total 47.63

Example 5: Development of an Optimized In Vitro Dissolution Method

Based on Compound (I) PK profiles obtained with MIN-101 MR 32 mg tabletsused in clinical studies, an in vitro/in vivo correlation (IVIVC)approach was proposed. The IVIVC approach is defined by the FDA as apredictive mathematical model describing the relationship between anin-vitro property of the dosage form and an in-vivo response. In thiscontext, the model refers to the relationship between the in vitrodissolution of the MR 32 mg tablet and its in vivo response such asCompound (I) plasma concentration. The main objectives of the IVIVCmodel were to validate the use of a predictive in-vitro dissolutionmethod and to select target optimized formulations. If the validity ofthe IVIVC model is confirmed by clinical results, the in-vitrodissolution method could be used as a surrogate method for clinicalstudies.

First, after analysis of all PK data for Compound (I) from clinicalstudies, an in-vitro dissolution profile of the MR 32 mg tabletdescribed in Example 1 was defined. This target in-vitro dissolutionprofile was then used to develop an optimized in-vitro dissolutionmethod. This method is described in the next Example.

Secondly, and when the in-vitro dissolution method was considered asclosed enough to the expectations, the target in-vitro dissolutionprofile of a gastro-resistant CR oral dosage form was defined and usedto design the gastro-resistant dosage forms described in Examples 2 and3. The dissolution profiles for these two GR dosage forms (GR-01 andGR-02) and the MR 32 mg tablet of Example 1, which were generated usingthe optimized dissolution method, are shown in tables 6 and 7 below.

TABLE 6 Cumulative In Vitro Dissolution Profiles Cumulative Dissolutionof Compound (I) (mg) Time Target MR 32 mg GR-01 GR-02 (hours) profiletablet tablet tablet 0 0 0  0 0 0.5 0  3.2 0 0 1 0  5.0 0 0 2 0  8.4 0 02.5 0.2 — 0 0 3 0.9 10.4 2.3 0.1 4 3.2 14.5 5.6 0.9 5 5.2 — — 2.6 6 7.119.4 9.9 4.5 8 11.0 23.1 12.9 8.1 10 14.8 — — — 11 — 27   18.2 12.6 1319.5 28.6 22.0 15.4 14 20.8 — — — 15 21.9 — — — 16 — 30.1 25.9 18.6 1825.0 — — — 19 — 30.6 28.2 21.1 21 27.6 — 22.8 26 31.6 30.1 24.6

TABLE 7 In Vitro Dissolution Rate Profiles Compound (I) Dissolution Rate(mg/hour) Time Target MR 32 mg GR-01 GR-02 (hours) Profile tablet tablettablet 0 0 0   0 0 0.5 0 6.4 0 0 1 0 3.7 0 0 2 0 2.7 0 0 2.5 0.4 — 0 0 31.5 2.0 2.3 0.1 4 2.3 4.1¹ 3.3 0.8 5 2.0 2.4¹ — 1.7 6 1.9 — 2.2 2 8 1.91.9 1.5 1.8 10 1.9 — — 1.5 11 — 1.3 1.8 — 13 1.6 0.8 1.9 1.4 14 1.3 — —— 15 1.2 — — — 16 0.5 1.3 1.1 18 1.0 — — 0.9 19 0.2 0.7 0.9 21 0.9 — 0.924 0.8 0.4 ¹not considered

The CR GR-01 and CR GR-02 tablets and the MR 32 mg tablet, used as acomparator, were tested in a clinical study (MIN-101-C06) to evaluatethe plasma PK profile of each dosage form.

Example 6: Analytical Method for the Assay of MIN-101, BFB-520 andBFB-999 in Human Plasma

Preparation of Solvents and Reagents

-   -   All solvents and reagents listed below are recognized as        analytical grade or better (relevant for the entire document).    -   Volumes are indicated as examples, different volumes may be        prepared if proportions are kept.

Dilution Solvent: 50/50 (v/v) Acetonitrile/Water Solution

-   -   Mix 500 mL of acetonitrile with 500 mL of water.

Storage:

1 month at room temperature.

Buffer: pH 9 Buffer Solution

-   -   Transfer the content of an ampoule of pH 9 buffer concentrate        (Merck, P/N 109889) in a 500 mL    -   volumetric flask.    -   Fill up q.s. 500.0 mL with water.

Storage:

1 month at ca. +5° C.

Buffer: 1 M Ammonium Acetate Buffer

-   -   Dissolve 7.7 g of ammonium acetate with 100 mL of water.

Storage:

3 months at ca. +5° C.

Mobile Phase: 10 mM Ammonium Acetate Buffer Solution

-   -   Add 10 mL of 1 M ammonium acetate buffer to 990 mL of water.    -   Or dissolve 0.77 g of ammonium acetate with 1 L of water.    -   Degas if necessary (by sonication or by magnetic agitation under        vacuum).

Storage:

5 days at room temperature.

Reconstitution Solvent: 80/20 (v/v) 10 mM Ammonium AcetateBuffer/Acetonitrile Solution

-   -   Mix 400 mL of 10 mM ammonium acetate buffer solution with 100 mL        of acetonitrile.    -   Or add 4 mL of 1 M ammonium acetate buffer to 396 mL of water        and 100 mL of acetonitrile.

Storage:

5 days at room temperature.

Needle Rinsing Solvent: 80/20 (v/v) Acetonitrile/Water Solution

-   -   Mix 800 mL of acetonitrile with 200 mL of water.    -   Degas if necessary (by sonication or by magnetic agitation under        vacuum).

Storage:

1 month at room temperature.

Needle Rinsing Solvent: 65/35 (v/v) Acetonitrile/Water Solution

-   -   Mix 650 mL of acetonitrile with 350 mL of water.    -   Degas if necessary (by sonication or by magnetic agitation under        vacuum).

Storage:

1 month at room temperature.

Column Rinsing Solvent: 90/10 (v/v) Acetonitrile/Water Solution

-   -   Mix 900 mL of acetonitrile with 100 mL of water.    -   Degas if necessary (by sonication or by magnetic agitation under        vacuum).

Storage:

1 month at room temperature.

Sample Preparation and Extraction Procedure

-   -   Control plasma and plasma samples are thawed at room temperature        and centrifuged at 1920 g for 5 minutes at +4° C.

Preparation of Samples

Blank Reagent Sample

In a 10 mL polypropylene tube:

-   -   1. Transfer 250 μL of water.

Blank and Zero Samples

In a 10 mL polypropylene tube:

-   -   1. Transfer 250 μL of control plasma.

Calibration Standards

In a 1.5 mL conic polypropylene tube:

-   -   1. Transfer 900 μL of control plasma,    -   2. Add 100 μL of appropriate WS,    -   3. Mix on a vortex for 30 seconds,    -   4. Transfer 250 μL of the preparation into a 10 mL polypropylene        tube.

QC Samples

In a 1.5 mL conic polypropylene tube:

-   -   1. Transfer 900 μL of control plasma,    -   2. Add 100 μL of appropriate QC-WS,    -   3. Mix on a vortex for 30 seconds,    -   4. Transfer 250 μL of the preparation into a 10 mL polypropylene        tube.

Specimens

In a 10 mL polypropylene tube:

-   -   1. Transfer 250 μL of plasma sample.

20-Fold Diluted Samples [2]

In a 1.5 mL conic polypropylene tube:

-   -   1. Transfer 380 μL of control plasma,    -   2. Add 20 μL of plasma sample to be diluted,    -   3. Mix on vortex for 30 seconds,    -   4. Transfer 250 μL of the preparation into a 10 mL polypropylene        tube.

Extraction Procedure

-   -   1. Add 25 μL of dilution solvent (blank reagent sample, blank        sample) or 25 μL of IS-WS (other samples),    -   2. Add 1 mL of pH 9 buffer solution,    -   3. Mix on a vortex for 10 seconds,    -   4. Add 4 mL of diethylether,    -   5. Mix on a reciprocating shaker at slow speed for 20 minutes,    -   6. Centrifuge at 1920 g for 10 minutes at +4° C.,    -   7. Transfer the tubes at ca. −80° C. for 15 minutes,    -   8. Transfer the organic phase (upper phase) into a 5 mL glass        tube,    -   9. Evaporate to dryness under a stream of nitrogen at +30° C.,    -   10. Reconstitute with 200 μL of reconstitution solvent,    -   11. Mix on a vortex for 30 seconds    -   12. Centrifuge at 1920 g for 5 minutes at +4° C.,    -   13. Transfer the final extract into a polypropylene vial,    -   14. Seal the vial with a cap with Teflon/silicone/Teflon septum,    -   15. Centrifuge at 2500 g for 7 minutes at +4° C.,    -   16. Place the vials in the autosampler until analysis.    -   Or [4]    -   13. Transfer the final extract into a 2 mL polypropylene        96-wells collection plate,    -   14. Seal the plate with a silicone pre-pierced cap mat,    -   15. Centrifuge at 2500 g for 7 minutes at +4° C.,    -   16. Place the plate in the autosampler until analysis.

Analysis Conditions

Chromatographic Conditions

Column and Oven

Column Gemini C18 100 × 4.6 mm, 3.0 μm (Phenomenex) Filler or guardcolumn C18 4 × 2 mm (Phenomenex) Column temperature +40° C. ± 5° C.Column rinsing solvent 90/10 (v/v) Acetonitrile/water solution Columnrinsing conditions 60 minutes at 0.6 mL/min

Autosampler

Injection volume 5 μL (to be adapted according to MS sensitivity)Autosampler +5° C. temperature

Pump

Mobile phase A 10 mM Ammonium acetate buffer solution Mobile phase BAcetonitrile

Isocratic Mode

Flow rate (mL/min) Mobile phase A(%) Mobile phase B (%) 0.6 35 65

Detection

Detection type MRM Ionisation type and mode ESI in positive ionisationmode Precursor ion [M + H]⁺

MRM Transitions

Analyte MRM transition MIN-101 (CYR-101) 367 > 146 BFB-520 369 > 146BFB-999 383 > 232 CYR-101-d6 373 > 152 BFB-784 387 > 164

LC Equipment No. 1

Description

Equipment Type Autosampler G1367B autosampler and G1330B thermostat(Agilent) LC pump G1311A quaternary pump and G1322A degasser (Agilent)Column oven G1316A thermostatted column compartment (Agilent) DetectorEP10⁺ HSID⁺⁺ (Ionics)

System Care

Needle rinsing solvent 80/20 (v/v) Acetonitrile/water solution

Needle Rinsing Programming

Step Description 1 Wash needle in flush port for 15 seconds 2 Drow defamount from sample, 200 μL min, 1 mm offset 3 Wash needle in flush portfor 15 seconds 4 Inject 5 Remote start pulse, duration 10 × 12.5 msec

Analysis Conditions

Injection volume   5 μL Run time 6.0 min

Retention Times (R_(t))

Analyte Rt (min) MIN-101 (CYR-101) ca. 2.9 BFB-520 ca. 2.3 BFB-999 ca.2.4 CYR-101-d6 ca. 2.9 BFB-784 ca. 2.4

LC Equipment No. 3 [5]

Description

Equipment Type Autosampler Acquity UPLC Sample Manager FTN (Waters) LCpump Acquity UPLC 1-Class (Waters) Column oven Acquity UPLC ColumnHeater (Waters) Detector XevoTQ-S (Waters)System CareNeedle Rinsing Solvent

Exterior (Wash) 80/20 (v/v) Acetonitrile/water solution Interior (Purge)65/35 (v/v) Acetonitrile/water solution Needle rinsing programmingPre-injection wash: 0 second

-   -   Post-injection wash: 6 seconds

Analysis Conditions

Injection volume 0.5 μL Run time 6.0 min

Retention Times (Rt)

Analyte Rt (min) MIN-101 (CYR-101) ca. 3.0 BFB-520 ca. 2.4 BFB-999 ca.2.4 CYR-101-d6 ca. 2.9 BFB-784 ca. 2.5

LC Equipment No. 2 [3]

Description

Equipment Type Autosampler Acquity UPLC (Waters) LC pump Column ovenAcquity UPLC high temperature column heater (Waters) Detector API 4000(AB Sciex)System CareNeedle Rinsing Solvent

Strong solvent 80/20 (v/v) Acetonitrile/water solution 2000 μL Weaksolvent 65/35 (v/v) Acetonitrile/water solution 4000 μLAnalysis Conditions

Injection volume   1 μL Injection mode Partial loop Run time 6.0 min

Retention Times (R_(t))

Analyte Rt (min) MIN-101 (CYR.-101) ca. 2.9 BFB-520 ca. 2.3 BFB-999 ca.2.4 CYR-101-d6 ca. 2.9 BFB-784 ca. 2.4

Data Processing and Acceptance Criteria

Data Processing [2]

MIN-101 (CYR-101) BFB-520 BFB-999 Calibration LLOQ  0.2500  0.2500 0.2500 range (ng/mL) ULOQ 200.0 50.00 50.00 (ng/mL) Response MIN-101peak BFB-520 BFB-999 area/CYR-101- peak area/ peak area/ d6 peak areaBFB-784 BFB-784 peak area peak area Regression model 1/X² weighted 1/X²weighted 1/X² weighted simple linear simple linear simple linearregression regression regression

Example 7: Synopsis of Protocol MIN-101C06

Name of Sponsor/Company:

Minerva Neurosciences, Inc.

Name of Investigational Product:

MIN-101

Study Title:

A Phase 1, Open-Label, Randomized, 3-Treatment Sequence, 3-Period,Single-Dose, Crossover Study in CYP2D6 Extensive Metaboliser HealthySubjects to Compare the Pharmacokinetic Properties of 2 Gastro-Resistantand 1 Comparator Modified Release Formulations of MIN-101 and itsMetabolites Followed by Food Effect Testing of the SelectedGastro-Resistant Controlled Release Formulation

Objectives:

Primary:

Part 1: PK Evaluation

-   -   To evaluate the pharmacokinetic (PK) profiles of MIN-101 and its        main metabolites (BFB-520 and BFB-999) following administration        of 2 Gastro-Resistant and 1 Comparator Modified Release (MR)        formulations of MIN-101 in healthy cytochrome P450 (CYP) 2D6        Extensive Metaboliser (EM) male and female subjects    -   To Select 1 gastro-resistant MR formulation for use in fed        state.        Part 2: Food Effect    -   To evaluate the effect of food (given as a high fat, high        calorie meal) on the bioavailability of MIN-101 and its main        metabolites when the selected gastro-resistant MR formulation is        administered as a single dose of 32 mg to healthy CYP2D6 EM male        and female subjects.        Secondary:        Part 1: PK Evaluation    -   To provide additional information on the safety and tolerability        of single doses of MIN-101 in healthy CYP2D6 EM male and female        subjects.    -   To evaluate the relationship between plasma levels of MIN-101        and its main metabolites on electrocardiogram (ECG) parameters        including QT/QTcF        Part 2: Food Effect    -   To evaluate the safety and tolerability of the selected MR        formulation in healthy CYP2D6 EM male and female subjects in fed        as compared to fasted state.        Methodology:        This is a single-center, 2-part, phase 1 study.        Part 1: PK Evaluation        Part 1 is an open-label, randomised, 3-treatment sequence,        3-period study to evaluate the PK profile of MIN-101 and its        metabolites (BFB-520 and BFB-999) after single oral        administration of 3 formulations of MIN-101 (2 prototypes of CR        gastro-resistant (GR) formulations and 1 comparator MR        formulation). Each subject will receive a single dose of each of        the formulations over the 3 periods. There will be a washout of        14±2 days between the three periods.        In total, 16 healthy CYP2D6 EM male or female subjects (with an        ideal equal gender split, but a minimum of 6 of each sex) will        be dosed to ensure data in 12 evaluable subjects. To be        evaluable, subjects must have received all 3 formulations and        have sufficient data for the primary objective of Part 1 of the        study. Subjects must provide written informed consent to        participate in the study before evaluations are performed or any        laboratory samples are collected. Subjects will be evaluated for        study eligibility during the screening period. After written        informed consent is obtained, a complete medical history will be        documented. A complete physical examination will be conducted,        including measurement of vital signs, ECG (triplicate), body        weight, and height. Hematology, clinical chemistry and        urinalysis will be performed for all subjects. All subjects must        be willing to use an acceptable double-barrier method of birth        control with their partners from Screening through 90 days after        the last dose.        Part 2: Food Effect        Subjects who completed part 1 of the study will return and        receive a further single oral dose of one of the selected GR        prototype under fed conditions to allow the assessment of food        effect by comparison of the PK properties to those obtained in        Part 1. Part 2 will commence after a review of the PK and safety        data to decide which GR formulation will be used. There will be        a wash-out period of 14±2 days after part 1 has been completed.        The end-of-study or early withdrawal assessments will be        performed 5-9 days after the last received dose.        Number of Subjects (Planned):        In total, 16 healthy CYP2D6 EM male or female subjects (with an        ideal equal gender split, but a minimum of 6 of each sex) will        be dosed to ensure data in 12 evaluable subjects.        Subjects who are withdrawn for non-IMP related adverse events        (AEs) will be replaced as required to ensure 12 evaluable        subjects for Part 1 and for Part 2, at the end of the clinical        study.        Subjects withdrawn due to an IMP-related AE will not be        replaced.        Diagnosis and Main Criteria for Inclusion/Exclusion:        Inclusion Criteria        Subjects must satisfy all of the following inclusion criteria        during screening to be enrolled in the study:    -   1. Confirmed CYP 2D6 extensive metaboliser genotype defined as a        subject that has at least one functional allele (*1, or *2) but        has no non-functional allele, meaning any combination of *1 and        *2, and a decreased function allele (*10, *17 or *41) is allowed        via documented testing    -   2. Subject has given voluntary written informed consent before        performance of any study related procedure    -   3. Must be 18 to 45 years of age, inclusive    -   4. Subject must be a healthy male or female as indicated by the        following:        -   Clinical chemistries, haematology, and urinalysis tests must            be within normal, allowable limits (if out of range, and            with the exception of potassium, magnesium, and calcium,            must be considered clinically significant to be            exclusionary) and performed within 21 days of receiving            first dose of study drug            -   Body mass index of between 18 and 30 kg/m², inclusive            -   Normal vital signs after 5 minutes resting in supine                position:                -   95 mm Hg<systolic blood pressure<140 mm Hg                -   50 mm Hg<diastolic blood pressure<90 mm Hg                -   50 bpm<heart rate<90 bpm                -   Normal 12-lead ECG defined as: P≤120 ms, 120                    ms<PR<210 ms, QRS                -    <120 ms, QTc (Fridericia)≤430 msec for males and                    ≤440 msec for females (incomplete right bundle                    branch block can be accepted)    -   5. Agree to abstain from all medication (except for allowed        birth control defined in inclusion criteria 6), including        non-prescription and prescription medication (including vitamins        and natural or herbal remedies, e.g. St. John's Wort) for 21        days before the first dose with IMP on period 1 until discharged        from the study (end of post study medical following period 4)    -   6. Subject agrees to use the following methods of birth control:        -   Female subjects of child bearing potential must be willing            to use two methods of contraception throughout and up to 30            days after completion of the study. One of which must be a            highly effective method defined as one which results in a            low failure rate (i.e. less than 1% per year) when used            consistently and correctly.        -   The following highly effective contraception methods            acceptable for this study are:            -   Surgical sterilization (i.e., bilateral tubal                ligation/salpingectomy, hysterectomy for female subjects                or partners; vasectomy for male subjects or partners)            -   Placement of an intrauterine device or intrauterine                system            -   Hormonal contraception (implantable, patch, injectable)        -   PLEASE NOTE: Oral hormonal contraceptives are not permitted            in this study.            -   True sexual abstinence when this is in line with the                preferred and usual lifestyle of the subject, periodic                abstinence (e.g. calendar ovulation, symptothermal,                post-ovulation methods), declaration of abstinence for                the duration of the trial and withdrawal are NOT                acceptable methods of contraception)                The following acceptable methods can be used as a second                form of contraception during the study:    -   Barrier methods for female subjects include either their        partner's use of a condom or the subject's use of an occlusive        cap [diaphragm or cervical/vault caps] with spermicidal foam,        gel, film, cream, or suppository    -   Female subjects who are post-menopausal (defined as spontaneous        amenorrhea for at least 1 year or spontaneous amenorrhea for at        least 6 months confirmed by Follicle stimulating hormone [FSH]        result of ≥40 IU/mL) are eligible for this study.

Male Subjects

-   -   Male subjects who have been sterilised or have partners of        non-childbearing potential (including homosexual men) are        required to use one barrier method of contraception. This is to        prevent unintended exposure of the partner to the study drug via        seminal fluid (for male subjects, this must be a condom or their        partner's use of an occlusive cap [diaphragm or cervical/vault        caps].    -   Male subjects who have partners of childbearing potential must        be willing to use one barrier method of contraception with their        partners throughout the study (a condom or their partner's use        of an occlusive cap [diaphragm or cervical/vault caps]). Their        partners must also be using a highly effective method of birth        control defined as one in which results in a low failure rate        (i.e. less than 1% per year) when used consistently and        correctly such as sterilisation, implants, injectables, combined        oral contraceptives, and intrauterine devices for up to 90 days        after completion of the study. Subjects must agree to inform the        Investigator if their partner becomes pregnant during this time.    -   7. Must be willing and able to communicate and participate in        the whole study.    -   8. Willing to eat all the food supplied throughout the study        Exclusion Criteria        Subjects meeting any of the following exclusion criteria are not        to be enrolled in the study:

-   1. A history of clinically significant gastrointestinal disease    (especially peptic ulcerations, gastrointestinal bleeding,    ulcerative colitis, Crohn's disease or Irritable Bowel Syndrome);    renal, hepatic, neurologic, hematologic, endocrine, oncologic,    pulmonary, immunologic or psychiatric disease (especially those with    a past history of clinically significant depression, suicidal    ideation or suicide attempts), or cardiovascular disease, or any    other condition which, in the opinion of the principle investigator,    would jeopardize the safety of the subject or impact the validity of    the study results

-   2. Acute diarrhea or constipation in the 7 days before the predicted    first study day. If screening occurs >7 days before first study day,    this criterion will be determined on first study day. Diarrhea is    defined as the passage of liquid feces and/or a stool frequency of    -   >3 times per day. Constipation will be defined as a failure to        move the bowels more frequently than every other day

-   3. Subject has donated blood within 90 days or plasma within 30 days    of study dosing

-   4. Regular alcohol consumption in males >21 units per week and    females >14 units per week (1 Unit=½ pint beer, 25 mL of 40% spirit    or a 125 mL glass of wine)

-   5. Subject has a borderline or long QTc Fridericia interval as    defined by screening readings of >430 msec for males and >440 for    females or a personal or familial history of long QT syndrome

-   6. Subject has participated in a clinical trial within 90 days prior    to study initiation

-   7. Females who are pregnant or breast feeding

-   8. Subject has used any prescription medication or over-the-counter    (OTC) medication, including vitamin supplements, within 21 days    prior to day −1

-   9. Subject has been treated with any known P450 2D6 or 3A4 enzymes    altering drugs (e.g., beta blockers, antidepressants,    antipsychotics, certain antibiotics such as erythromycin,    ketoconazole, rifampicin, trimethoprim or clarithromycin,    benzodiazepine such as alprazolam or midazolam, antihistamines such    as chlorpheniramine, calcium channel blockers such as amlodipine or    diltiazem, or PDE5 inhibitors) within 30 days prior to the study

-   10. Subject has smoked or used nicotine products within 2 months    prior to or during the study

-   11. Subject has sought advice from or been referred to a GP or    counsellor for abuse or misuse of alcohol, non-medical drugs,    medicinal drugs or other substance abuse, e.g. solvents

-   12. Subject has a positive blood screen for HIV, Hepatitis B surface    antigen (HBsAg), and Hepatitis C Antibody

-   13. Any current or previous use of drugs such as opiates, cocaine,    ecstasy, or intravenous amphetamines and/or a positive urine screen    for alcohol or drugs of abuse. Subjects who admit to occasional past    use of cannabis will not be excluded as long as they have a negative    drugs-of-abuse test and have been abstinent from cannabis use for at    least 3 months

-   14. Subject has a current uncontrolled inter-current illness (i.e.,    active infection) or has had a clinically significant illness within    the last 30 days prior to Day −1

-   15. Subject has had major surgery within 28 days of study entry, or    12 months prior to study for gastrointestinal surgery.

-   16. Failure to satisfy the investigator of fitness to participate    for any other reason.    Test Product, Dosage, and Route of Administration:    Part 1:    After fasting for 10 hours overnight, on the morning of dosing days,    study drug will be administered with 240 mL of noncarbonated water.    Subjects will have their first meal at lunch time. Subjects will    receive a single oral administration of each of the following    regimens in a randomized manner, separated by a 14±2 days washout    period:    Regimen A: 32 mg MIN-101 of the current modified-release formulation    (comparator) identified as MR-32 formulation administered in the    fasted state    Regimen B: 32 mg MIN-101 of Gastro-resistant CR Formulation    identified as GR-01: administered in the fasted state    Regimen C: 32 mg MIN-101 of Gastro-resistant CR Formulation    identified as GR-02: administered in the fasted state    Part 2:    In Part 2, subjects will receive 1 oral dose of the selected    gastro-resistant CR formulation (GR-01 or GR-02) in the fed state.    After fasting for 10 hours overnight, on the morning of Day 1,    subjects will be given a high-fat, high-calorie breakfast before    study drug administration. Subjects will consume the meal over a    25-minute period or less. After completing the meal, and 30 minutes    after the start of the meal, study drug will be administered.    All study drugs will be administered orally with 240 mL of    noncarbonated water. Water will be allowed as desired except for 1    hour before and 1 hour after drug administration.    Reference Therapy, Dosage and Mode of Administration:    Not Applicable. 32 mg MIN-101 of the current modified release    formulation to be used as a comparator.    Duration of Subject Participation/Duration of Study/Duration of    Treatment:    Selection:    Up to 21 days prior to first dose period 1    Institutionalization:    From morning of Day −1 up to Day 4 for 4 separate periods    Washout Period:    14±2 days from previous period dosing    End-of-Study Visit:    7 (+2 days) days after the last dose    Total Study Length (Including a Screening Period of 21 Days):    Up to 78 Days.    Evaluation Criteria    Pharmacokinetics:    Plasma will be stored at −80° C. until analysis. Plasma samples will    be analyzed for MIN-101 and its metabolites BFB-520 and BFB-999    using a validated LC-MS/MS method.    Blood samples for MIN-101 will be collected at time 0 (pre-dose),    0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5,    6, 7, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 48, 60, and 72 hours    post-dose on Day 1 of all periods. The following key plasma PK    parameters will be calculated using non-compartmental methods:    C_(max), T_(max), T_(lag), partial AUC (e.g., AUC₁₂, AUC₂₄),    AUC_(last), AUC_(∞), and t_(1/2). Additional PK parameters may be    included if deemed appropriate.    ECG to be Detailed as there Will be PK/PD Assessment    The effects on cardiovascular variables will be evaluated by means    of descriptive statistics and frequency tabulations. These tables    will include observed values and changes from Baseline values (the    pre-dose ECG will be used as Baseline) to allow detection of    clinically relevant changes in individuals.    The ECG variables that will be analyzed are heart rate, PR interval,    QRS interval, QT interval, and QTc interval corrected for heart rate    using QTcF. QTcF values will be tabulated for their absolute values    and also tabulated relative to Baseline measurements in order to    detect individual QTcF changes.    Descriptive statistics of QTcF intervals and changes from Baseline    will be summarised at each scheduled time point. The percent of    subjects with QTc interval ≥450 milliseconds, >480 milliseconds, or    ≥500 milliseconds will be summarised as will the percent of subjects    with QTcF interval increases from Baseline of 30 to 59 milliseconds    or ≥60 milliseconds.    Important abnormalities in ECG waveform that are changes from the    Baseline readings will be reported (e.g., changes in T-wave    morphology or the occurrence of U-waves).    Safety and Tolerability:    The incidence of adverse events and clinically significant abnormal    laboratory, vital signs and ECGs values will be recorded based upon    Investigator observation and subject reporting.    Statistical Considerations    Sample Size:

The sample size for this study is based upon both quantitative andqualitative consideration. In previous single dose experience with EMsubjects, the inter-subject coefficient of variance (CV) for plasma AUCand C_(max) for MIN-101 reference formulation is estimated to be about30% and 50%, respectively. Therefore, the selected sample size of 12 to16 completers should be sufficient to address the objectives of thisstudy and to detect the occurrence of rare adverse events should suchevent are likely due to treatment with MIN-101. Every effort will bemade to have an equal number of males and females enrolled.

Pharmacokinetics:

Pharmacokinetic parameters will be summarized by mean, standarddeviation, standard error of the mean, coefficient of variation,minimum, median, and maximum, as appropriate, for each formulation andbetween the selected MR formulation for each food condition. The 90%confidence intervals for the ratio of mean log-transformed plasmapartial AUC, AUC_(last), and AUC_(∞) and C_(max) will be constructedusing the estimated least squares means and intra-subject variance froma mixed effects model.

Additional analysis will be performed if deemed necessary including therelationship between plasma levels of MIN-101 and its main metabolitesand changes in QTcF intervals.

Safety:

Safety and tolerability of MIN-117 will be based upon the review ofindividual values and summary statistics. Incidence oftreatment-emergent adverse events will be tabulated by counts andpercentages. Abnormalities in clinical laboratory, vital signs, and ECGwill be based on pre-defined normal ranges and will be tabulated by dosegroup showing subject counts and percentages.

Examples 8-11 detail an open-label, randomized, 3-treatment sequence,3-period study to evaluate the PK profile of MIN-101 and its metaboliteBFB-520 after single oral administration of 3 formulations of MIN-101 (2prototypes of CR gastro-resistant (GR) formulations (GR-01 and GR-02)and 1 comparator MR formulation (MR32)). Each subject received a singledose of each of the formulations over the 3 periods. There was a washoutof 14±2 days between the three periods.

In the Examples, various tables are shown which include the plasmaconcentrations time profile of various compounds, including, forexample, 1H-Isoindol-1-one,2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-,i.e., Compound (I). In these Tables, the use of the “MIN-101” or“MIN101” is intended to refer to the free base, i.e., Compound (I).

Example 8: In Vivo Pharmacokinetic Analysis of MIN-101 in CR GR-01Tablets, CR GR-02 Tablets, and MR 32 mg Capsules (MR32) (Tau=72 h)

MR32—

12 subjects (cross-over)

Geo Mean C_(max): 28.34 ng/mL

Median T_(max): 2.00 H

AUC_((0-tau)): 291.55 ng·H/mL

TABLE 8 MR32 Mean MIN-101 Plasma Concentrations and Parameters MR32MIN-101 PLASMA MR32 CONCENTRATIONS and AUCo-t Hours MEAN Sd Sm CV % 00.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.5 6.56 7.42 6.46 113.08 119.68 7.24 5.44 36.77 1.5 23.96 7.68 6.33 32.04 2 24.16 7.89 5.97 32.642.5 24.68 6.47 5.19 26.24 3 22.06 5.41 4.71 24.54 3.5 20.34 5.38 4.2126.46 4 19.45 5.61 4.92 28.83 5 21.54 10.08 7.17 46.80 6 15.19 6.89 4.9145.33 7 11.89 5.89 3.82 49.52 8 10.36 4.69 3.39 45.27 10 12.46 5.94 4.9547.65 12 12.66 5.64 4.41 44.58 14 10.33 4.86 3.96 47.05 16 7.74 3.142.64 40.56 20 4.12 2.26 1.85 54.83 24 3.11 1.62 1.48 52.21 28 2.39 2.241.38 93.57 32 1.45 1.42 0.96 97.56 36 0.96 1.15 0.65 119.73 48 0.20 0.350.27 176.68 60 0.03 0.12 0.06 346.41 72 0.04 0.13 0.07 346.41 CMax ng/ml29.52 9.00 6.70 30.48 Tmax H 2.42 1.33 0.99 54.98 AUC0-t 291.55 66.1253.61 22.68 H · ng/ml

See FIG. 4.

GR-01-12 subjects (cross-over)

Geo Mean C_(max): 18.82 ng/mL

Median T_(max): 4.50 H

AUC_((0-tau)): 284.52 ng·H/mL

Relative Bioavailability versus MR32: F % C_(max): 69.90%, F %AUC_((0-tau)): 101.3%

TABLE 9 GR-01 Individual MIN-101 Plasma Concentrations and ParametersGR01 MEAN MIN-101 PLASMA CONCENTRATIONS (ng/ml) and AUCo-t (H · ng/ml)1- 2- 3- 5- 6- 7- 8- 9- 10- 11- 12- 13- GR01 MIN- MIN- MIN- MIN- MIN-MIN- MIN- MIN- MIN- MIN- MIN- MIN- Hours 101 101 101 101 101 101 101 101101 101 101 101 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 4.22 0.00 0.00 0.00 1.5 0.00 0.006.26 0.00 0.00 0.00 0.38 0.00 0.42 0.00 0.00 7.98 2 3.83 5.42 10.68 2.500.00 0.00 13.23 0.00 8.71 16.03 0.48 8.14 2.5 15.95 13.82 11.87 12.140.00 3.45 12.42 3.00 12.78 24.17 23.30 7.62 3 17.85 17.61 11.10 13.880.39 12.78 11.08 24.02 12.98 26.68 28.00 10.13 3.5 15.56 21.53 10.9712.31 6.52 10.89 10.94 28.19 13.60 25.78 24.01 12.18 4 20.60 19.03 8.2311.96 15.23 9.53 8.04 22.91 17.64 24.78 22.59 11.30 5 17.05 17.24 6.6614.68 15.63 8.44 14.90 17.95 12.92 24.46 12.86 12.69 6 15.26 14.41 6.8913.19 13.39 6.06 12.36 11.72 7.62 19.24 5.64 10.42 7 9.61 11.29 6.2812.62 10.60 4.71 11.51 13.95 6.70 17.83 9.72 9.08 8 7.46 7.20 5.58 11.8610.51 3.51 8.19 16.53 13.39 14.16 5.82 8.52 10 4.30 5.10 12.66 11.696.19 2.71 18.08 17.00 18.05 8.68 13.19 10.59 12 9.45 5.59 10.24 20.157.24 3.05 12.22 13.92 16.31 11.15 13.39 12.47 14 13.11 10.14 12.01 17.737.12 3.52 12.65 12.02 14.42 11.67 20.32 6.36 16 10.98 6.35 12.59 16.886.40 3.18 7.19 11.25 13.43 13.29 19.44 6.02 20 5.54 3.88 4.69 8.36 4.952.65 2.44 7.99 6.52 9.76 5.92 3.23 24 5.57 1.94 3.21 6.73 6.31 2.38 2.9012.21 3.90 10.97 3.63 7.08 28 4.31 1.64 3.18 2.55 3.91 2.35 1.47 7.673.79 10.31 0.54 5.80 32 3.50 1.56 2.73 1.16 3.55 5.90 0.66 3.59 2.797.59 0.67 3.46 36 2.37 1.06 1.34 0.54 2.14 12.25 0.00 1.06 0.56 3.730.37 3.60 48 1.33 0.73 0.28 0.00 2.04 2.55 0.00 0.00 0.00 0.56 0.00 1.7660 0.00 0.48 0.00 0.00 1.33 1.33 0.00 0.00 0.00 0.00 0.00 0.45 72 0.000.69 0.00 0.00 0.41 0.44 0.00 0.00 0.00 0.00 0.00 0.27 CMax 20.6 21.512.7 20.2 15.6 12.8 18.1 28.2 18.1 26.7 28.0 12.7 ng/ml Tmax H 4.0 3.510.0 12.0 5.0 3.0 10.0 3.5 10.0 3.0 3.0 5.0 AUC0-t 281.6 219.3 230.1309.7 262.8 257.0 213.8 357.2 289.7 430.4 279.0 283.6 H · ng/ml F AUC84.0 93.6 98.8 172.8 92.0 112.6 80.0 92.5 76.9 143.9 76.0 92.5 F Cmax65.3 72.9 48.6 110.5 54.2 69.1 74.4 66.4 37.7 116.9 76.9 45.7

TABLE 10 GR-01 Mean MIN-101 Plasma Concentrations and Parameters GR01MIN-101 PLASMA GR01 CONCENTRATIONS and AUCo-t Hours MEAN Sd Sm CV % 00.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 10.35 1.22 0.65 346.41 1.5 1.25 2.77 1.95 220.78 2 5.75 5.57 4.67 96.912.5 11.71 7.46 5.46 63.69 3 15.54 7.84 6.08 50.45 3.5 16.04 7.01 5.8943.68 4 15.99 6.08 5.27 38.00 5 14.62 4.60 3.26 31.47 6 11.35 4.17 3.3536.70 7 10.33 3.58 2.64 34.63 8 9.39 3.93 3.25 41.81 10 10.69 5.39 4.4250.45 12 11.26 4.66 3.48 41.34 14 11.76 4.67 3.33 39.73 16 10.58 4.873.96 46.01 20 5.49 2.33 1.85 42.48 24 5.57 3.30 2.58 59.31 28 3.96 2.802.04 70.67 32 3.10 2.06 1.50 66.68 36 2.42 3.33 2.05 137.50 48 0.77 0.920.77 119.51 60 0.30 0.51 0.40 171.48 72 0.15 0.24 0.20 159.83 CMax ng/ml19.59 5.74 4.61 29.30 Tmax H 6.00 3.43 3.00 57.19 AUC0-t H · ng/ml284.52 60.83 41.49 21.38 F AUC 101.30 29.16 20.90 28.79 F Cmax 69.9023.92 17.04 34.22

See FIG. 5.

GR-02-12 subjects (cross-over)

Geo Mean C_(max): 15.43 ng/mL

Median T_(max): 14.00 H

AUC_((0-tau)): 253.01 ng·H/mL

Relative Bioavailability versus MR32: F % C_(max): 54.33%, F %AUC_((0-tau)): 86.9%

TABLE 11 GR-02 Individual MIN-101 Plasma Concentrations and ParametersGR02 MEAN MIN-101 PLASMA CONCENTRATIONS (ng/ml) and AUCo-t (H · ng/ml)1- 2- 3- 4- 5- 7- 8- 9- 10- 11- 12- 13- 14- GR02 MIN- MIN- MIN- MIN-MIN- MIN- MIN- MIN- MIN- MIN- MIN- MIN- MIN- Hours 101 101 101 101 101101 101 101 101 101 101 101 101 0 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 1.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 2.03 2 0.00 0.00 0.41 0.00 0.70 0.00 0.00 0.00 0.000.00 0.00 0.88 6.86 2.5 2.13 0.00 1.87 0.00 1.17 1.09 0.00 1.24 2.481.02 0.00 2.79 11.97 3 4.71 0.41 2.66 0.00 2.98 1.52 0.66 2.55 2.87 5.064.14 2.81 11.48 3.5 6.35 1.16 3.08 0.35 2.16 2.14 1.06 3.14 5.27 11.727.24 3.02 14.23 4 8.70 2.20 3.06 1.17 2.19 2.25 1.21 3.45 6.24 12.698.58 3.45 12.39 5 8.93 6.06 3.40 3.00 10.46 2.87 2.49 4.07 7.52 14.537.76 8.84 11.67 6 7.60 6.39 2.61 2.92 10.83 3.37 1.94 4.24 6.94 11.335.09 8.09 81.75 7 5.96 5.09 3.56 5.85 7.32 3.15 2.06 4.52 4.85 10.765.23 9.19 8.67 8 5.11 4.28 2.89 5.14 6.40 3.30 2.58 5.76 5.02 6.39 11.438.98 10.06 10 4.90 3.27 3.92 5.82 12.63 4.26 3.26 9.25 5.39 10.25 12.9611.15 15.14 12 15.08 2.81 6.31 9.24 20.26 3.27 6.31 8.07 21.50 17.6813.88 16.18 25.98 14 11.62 7.94 7.57 10.68 18.73 3.42 3.77 10.16 11.1516.50 15.37 9.96 29.85 16 9.87 5.79 11.46 7.68 15.69 8.22 2.61 10.949.53 9.32 19.54 7.85 19.75 20 10.00 6.27 6.62 3.77 6.34 5.19 0.94 7.504.26 8.94 9.83 4.94 6.44 24 9.29 4.59 5.07 5.95 6.69 12.66 0.64 10.976.98 7.46 12.76 13.32 3.97 28 8.23 3.21 4.04 4.43 1.64 13.20 0.48 10.5610.72 6.28 10.99 7.05 3.54 32 8.21 4.06 2.61 3.35 0.44 6.48 0.00 7.929.55 3.03 4.75 4.90 1.38 36 4.24 2.75 1.59 2.12 0.00 2.87 0.00 4.57 4.941.66 2.00 3.42 0.40 48 1.72 0.93 0.58 0.58 0.00 0.43 0.00 0.91 0.00 0.550.29 0.54 0.00 60 0.00 1.34 0.41 0.00 0.00 0.00 0.00 0.65 0.00 0.00 0.000.31 0.00 72 0.00 0.28 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 CMax 15.1 7.9 11.5 10.7 20.3 13.2 6.3 11.0 21.5 17.7 19.5 16.2 29.9ng/ml Tmax H 12.0 14.0 16.0 14.0 12.0 28.0 12.0 24.0 12.0 12.0 16.0 12.014.0 AUC0-t 319.8 190.9 183.2 182.0 247.4 233.2 53.0 308.3 275.7 300.5357.4 298.6 338.9 H · ng/ml F AUC 95.4 81.5 78.6 101.6 86.6 102.2 19.879.9 73.2 100.5 97.3 97.5 116.3 F Cmax 47.8 26.9 44.0 58.6 70.3 71.426.0 25.8 45.0 77.5 53.7 58.3 101.1

TABLE 12 GR-02 Mean MIN-101 Plasma Concentrations and Parameters GR02MIN-101 PLASMA GR02 CONCENTRATIONS and AUCo-t Hours MEAN Sd Sm CV % 00.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 10.00 0.00 0.00 0.00 1.5 0.16 0.59 0.31 375.28 2 0.68 1.95 1.04 286.762.5 1.98 3.29 1.89 166.30 3 3.22 3.03 1.90 94.21 3.5 4.69 4.39 3.3893.69 4 5.20 4.14 3.38 79.73 5 7.05 3.94 3.24 55.85 6 6.16 3.20 2.6851.99 7 5.86 2.63 2.09 44.82 8 5.95 2.84 2.19 47.70 10 7.86 4.27 3.7954.29 12 12.81 7.69 6.62 60.04 14 12.06 7.28 5.35 60.38 16 10.63 5.243.98 49.25 20 6.23 2.37 1.75 37.95 24 7.72 4.01 3.23 52.01 28 6.49 4.153.47 63.88 32 4.36 2.90 2.24 66.52 36 2.35 1.62 1.26 69.09 48 0.50 0.340.29 68.40 60 0.21 0.41 0.30 197.87 72 0.02 0.08 0.04 375.28 CMax ng/ml15.43 6.70 5.37 43.38 Tmax H 15.23 5.20 3.67 34.12 AUC0-t H · ng/ml253.01 85.28 65.81 33.71 F AUC 86.94 24.39 16.36 28.05 F Cmax 54.3323.09 17.99 42.50

See FIG. 6.

TABLE 13 Comparison of MR32, GR-01, and GR-02 MIN-101 PlasmaConcentrations. MR32 GR01 and GR02 Mean MIN-101 Plasma Concentrations(ng/ml) Hours MR32-Mean GR01-Mean GR02-Mean 0 0.00 0.00 0.00 0.25 0.000.00 0.00 0.5 6.56 0.00 0.00 1 19.68 0.35 0.00 1.5 23.96 1.25 0.16 224.16 5.75 0.68 2.5 24.68 11.71 1.98 3 22.06 15.54 3.22 3.5 20.34 16.044.69 4 19.45 15.99 5.20 5 21.54 14.62 7.05 6 15.19 11.35 6.16 7 11.8910.33 5.86 8 10.36 9.39 5.95 10 12.46 10.69 7.86 12 12.66 11.26 12.81 1410.33 11.76 12.06 16 7.74 10.58 10.63 20 4.12 5.49 6.23 24 3.11 5.577.72 28 2.39 3.96 6.49 32 1.45 3.10 4.36 36 0.96 2.42 2.35 48 0.20 0.770.50 60 0.03 0.30 0.21 72 0.04 0.15 0.02 Max ng/ml 29.5 19.6 15.4 Tmax H2.4 6.0 15.2 AUC0-t H · ng/ml 291.6 284.5 253.01 F AUC REF 101.3 86.94 FCmax REF 69.9 54.33

See FIG. 7.

TABLE 14 Comparison of MR32, GR-01, and GR-02 MIN-101 PlasmaConcentrations - Rates of Increase and Decrease. MR32 and GR01 MeanMIN101 Plasma Conc. Rates of Increase and Decrease (ng/ml)/H HoursMR32-RATE GR01-RATE GR02-RATE 0 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.526.25 0.00 0.00 1 26.24 0.70 0.00 1.5 8.56 1.80 0.31 2 0.39 9.00 1.052.5 1.03 11.92 2.60 3 0.00 7.66 2.48 3.5 0.00 1.00 2.94 4 0.00 0.00 1.025 2.09 0.00 1.85 6 0.00 0.00 0.00 7 0.00 0.00 0.00 8 0.00 0.00 0.09 101.05 0.65 0.96 12 0.10 0.29 2.48 14 0.00 0.25 0.00 16 0.00 0.00 0.00 200.00 0.00 0.00 24 0.00 0.02 0.37 28 0.00 0.00 0.00 32 0.00 0.00 0.00 360.00 0.00 0.00 VMax (ng/ml)/H 26.2 11.9 2.9 Time of VMax 0.50 2.50 3.50TEST/MR32 REF 0.45 0.11

During each time interval (dt) the plasma concentration (C_(p)) ofMIN-101 increases or decreases. From t=0 to T_(max), the rate ofincrease V_(max)=d(C_(p))/dt. After the V_(max), the rates aredecreasing. See FIG. 8.

Example 9: In Vivo Pharmacokinetic Analysis of BFB-520 in CR GR-01Tablets, CR GR-02 Tablets, and MR 32 mg Capsules (MR32) (Tau=72 h)

MR32—

12 subjects (cross-over)

Geo Mean C_(max): 1.77 ng/mL

Median T_(max): 6.00 H

AUC_((0-tau)): 30.26 ng·H/mL

TABLE 15 MR32 Individual BFB-520 Plasma Concentrations and ParametersMR32 BFB-520 PLASMA CONCENTRATIONS (ng/ml) and AUCo-t (H · ng/ml) 1- 2-3- 5- 6- 7- 8- 9- 10- 11- 12- 13- MR32 BFB- BFB- BFB- BFB- BFB- BFB-BFB- BFB- BFB- BFB- BFB- BFB- Hours 520 520 520 520 520 520 520 520 520520 520 520 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 0.560.54 0.00 0.30 0.53 0.32 0.28 1.01 0.00 0.70 0.56 0.26 1.5 1.20 0.850.58 0.36 0.72 0.61 0.76 1.29 0.43 1.28 1.10 0.50 2 1.24 0.65 0.89 0.620.92 0.89 0.59 2.42 0.80 1.41 1.23 0.80 2.5 1.41 0.75 0.97 0.89 1.180.88 0.84 2.16 1.19 1.69 1.76 0.79 3 1.37 0.94 0.99 1.18 1.56 1.12 1.103.33 1.58 1.93 1.63 0.74 3.5 1.72 1.03 0.81 1.25 1.44 1.20 1.28 2.911.57 1.91 1.94 0.84 4 2.03 0.99 0.98 1.38 1.65 1.21 1.38 2.30 1.65 1.772.27 0.95 5 1.91 1.10 1.09 0.90 1.64 1.10 1.07 2.55 2.97 2.09 1.61 1.036 1.81 1.09 0.83 0.88 1.76 0.96 1.09 2.23 3.13 1.94 1.73 1.10 7 1.910.95 0.90 0.90 1.40 0.94 0.89 2.25 2.91 2.10 1.16 1.01 8 1.69 0.92 0.710.79 1.60 1.01 1.19 2.63 3.13 1.93 1.42 1.08 10 1.27 1.00 1.09 0.63 1.690.73 1.73 1.97 2.76 2.46 1.44 1.01 12 0.73 1.20 0.56 0.84 1.39 0.56 1.421.07 2.12 2.63 1.26 0.71 14 0.88 1.06 0.62 1.07 1.30 0.75 1.46 2.63 2.352.74 1.37 0.55 16 0.99 0.86 0.54 0.65 0.85 0.58 1.23 1.76 1.53 1.65 1.030.51 20 1.43 0.68 0.48 0.58 0.61 0.86 0.70 1.20 0.87 1.40 0.95 0.41 240.69 0.39 0.35 0.00 0.35 0.77 0.47 0.67 0.70 0.58 0.63 0.36 28 0.89 0.000.31 0.00 0.30 0.44 0.00 0.45 0.46 0.37 0.33 0.61 32 0.40 0.00 0.00 0.000.00 0.35 0.00 0.00 0.28 0.00 0.00 0.81 36 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.61 48 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 60 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 72 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 000 000 000Max 2.0 1.2 1.1 1.4 1.8 1.2 1.7 3.3 3.1 2.7 2.3 1.1 ng/ml Tmax H 4.012.0 10.0 4.0 6.0 4.0 10.0 3.0 6.0 14.0 4.0 6.0 AUC0-t 34.7 20.1 16.715.3 27.2 22.6 24.8 44.9 47.2 46.7 34.5 28.5 H · ng/ml

TABLE 16 MR32 Mean BFB-520 Plasma Concentrations and Parameters MR32BFB-520 PLASMA CONCENTRATIONS MR32 and AUCo-t Hours MEAN Sd Sm CV % 00.00 0.25 0.00 0.5 0.00 1 0.42 0.29 0.23 68.42 1.5 0.81 0.33 0.28 41.402 1.04 0.51 0.36 48.77 2.5 1.21 0.45 0.36 37.60 3 1.46 0.68 0.46 46.843.5 1.49 0.58 0.43 38.99 4 1.55 0.48 0.40 31.20 5 1.59 0.67 0.54 42.36 61.55 0.69 0.55 44.45 7 1.44 0.68 0.57 47.23 8 1.51 0.75 0.57 49.53 101.48 0.66 0.53 44.91 12 1.21 0.63 0.46 52.49 14 1.40 0.77 0.60 54.91 161.01 0.44 0.36 43.42 20 0.85 0.34 0.27 40.36 24 0.50 0.22 0.18 44.39 280.35 0.26 0.19 75.95 32 0.15 0.26 0.21 168.74 36 0.05 0.18 0.09 346.4148 0.00 60 0.00 72 0.00 Max ng/ml 1.91 0.80 0.65 41.65 Tmax H 6.92 3.653.06 52.84 AUC0-t 30.26 11.35 9.43 37.51 H · ng/ml

See FIG. 9.

GR-01-12 subjects (cross-over)

Geo Mean C_(max): 1.77 ng/mL

Median T_(max): 6.00 H

AUC_((0-tau)): 27.48 ng·H/mL

Relative Bioavailability versus MR32: F % C_(max): 80.48%, F %AUC_((0-tau)): 96.1%

TABLE 17 GR-01 Individual BFB-520 Plasma Concentrations and ParametersGR01 BFB-520 PLASMA CONCENTRATIONS (ng/ml) and AUCo-t (H · ng/ml) 1- 2-3- 5- 6- 7- 8- 9- 10- 11- 12- 13- GR01 BFB- BFB- BFB- BFB- BFB- BFB-BFB- BFB- BFB- BFB- BFB- BFB- Hours 520 520 520 520 520 520 520 520 520520 520 520 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1.5 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2 0.00 0.00 0.26 0.000.00 0.00 0.00 0.00 0.00 0.28 0.00 0.00 2.5 0.00 0.56 0.43 0.00 0.000.00 0.30 0.00 0.46 0.60 0.28 0.00 3 0.42 0.71 0.45 0.44 0.00 0.26 0.600.60 0.63 0.88 0.53 0.38 3.5 0.54 1.00 0.50 0.47 0.00 0.38 0.57 1.280.74 1.00 0.86 0.43 4 0.84 1.04 0.49 0.63 0.35 0.39 0.45 1.41 1.08 1.290.72 0.51 5 1.01 0.98 0.39 0.72 0.62 0.51 0.75 1.56 1.13 1.45 0.99 0.616 1.07 1.07 0.43 0.78 0.83 0.54 0.85 1.47 0.85 1.19 0.72 0.64 7 1.201.28 0.37 0.92 0.93 0.51 0.88 1.47 0.71 1.47 0.74 0.80 8 1.17 1.07 0.441.10 1.03 0.68 0.76 1.80 1.37 1.63 1.06 0.74 10 0.68 0.96 0.68 1.23 0.770.33 1.28 1.72 1.84 1.32 1.37 0.99 12 0.65 0.77 0.55 1.30 0.66 0.32 0.911.40 1.74 0.78 2.26 1.08 14 1.00 0.87 0.72 1.73 0.74 0.43 1.24 1.54 1.821.11 1.11 1.05 16 1.00 0.71 0.83 1.80 0.51 0.43 1.09 1.49 1.80 1.24 1.110.95 20 0.69 0.70 0.63 1.58 0.67 0.40 0.71 1.73 1.13 1.44 1.17 0.68 240.57 0.31 0.43 0.85 0.50 0.00 0.39 1.31 0.57 1.05 0.99 0.58 28 0.72 0.260.50 0.58 0.59 0.00 0.28 1.15 0.92 1.27 0.65 0.58 32 0.33 0.00 0.28 0.300.46 0.44 0.00 0.67 0.62 0.68 0.28 0.43 36 0.29 0.00 0.00 0.00 0.38 1.100.00 0.28 0.00 0.51 0.00 0.42 48 0.00 0.00 0.00 0.00 0.00 0.33 0.00 0.000.00 0.00 0.00 0.00 60 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 72 0.00 0.00 0.00 000 000 000 000 000 000 000 000 000 Max 1.21.3 0.8 1.8 1.0 1.1 1.3 1.8 1.8 1.6 2.3 1.1 ng/ml Tmax H 7.0 7.0 16.016.0 8.0 36.0 10.0 8.0 10.0 8.0 12.0 12.0 AUC0-t 23.5 18.6 16.1 31.319.7 19.0 19.6 43.8 36.1 40.6 33.7 27.9 H · ng/ml F AUC 67.7 92.5 96.3204.6 72.3 83.9 79.2 97.6 76.5 86.9 97.7 98.0 F Cmax 59.0 107.4 75.8131.0 58.6 90.8 73.6 54.0 58.8 59.7 99.6 97.5

TABLE 18 GR-01 Mean BFB-520 Plasma Concentrations and Parameters GR01BFB-520 PLASMA CONCENTRATIONS GR01 and AUCo-t Hours MEAN Sd Sm CV % 00.00 0.25 0.00 0.5 0.00 1 0.00 1.5 0.00 2 0.04 0.10 0.07 233.68 2.5 0.220.25 0.22 112.01 3 0.49 0.23 0.17 45.99 3.5 0.65 0.35 0.27 53.37 4 0.770.36 0.31 47.35 5 0.89 0.36 0.29 40.77 6 0.87 0.29 0.22 33.50 7 0.940.35 0.28 37.58 8 1.07 0.39 0.29 36.81 10 1.10 0.45 0.36 40.79 12 1.040.55 0.43 53.43 14 1.11 0.42 0.31 37.58 16 1.08 0.45 0.34 41.52 20 0.960.43 0.38 45.29 24 0.63 0.36 0.28 57.32 28 0.63 0.36 0.26 57.90 32 0.370.23 0.18 60.48 36 0.25 0.33 0.25 133.52 48 0.03 0.09 0.05 346.41 600.00 72 0.00 Max ng/ml 1.43 0.43 0.37 30.06 Tmax H 12.50 8.04 5.08 64.32AUC0-t H · ng/ml 27.48 9.46 8.07 34.41 F AUC 96.10 35.77 18.95 37.22 FCmax 80.48 24.60 20.65 30.56

See FIG. 10.

GR-02-12 subjects (cross-over)

Geo Mean C_(max): 1.13 ng/mL

Median T_(max): 16.00 H

AUC_((0-tau)): 27.53 ng·H/mL

Relative Bioavailability versus MR32: F % C_(max): 69.48%, F %AUC_((0-tau)): 88.46%

TABLE 19 GR-02 Individual BFB-520 Plasma Concentrations and ParametersGR02 BFB-520 PLASMA CONCENTRATIONS (ng/ml) and AUCo-t (H · ng/ml) 1- 2-3- 4- 7- 8- 9- 10- 11- 12- 13- 14- GR02 BFB- BFB- BFB- BFB- 5-BFB- BFB-BFB- BFB- BFB- BFB- BFB- BFB- BFB- Hours 520 520 520 520 520 520 520 520520 520 520 520 520 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 1.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 2.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.44 3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.26 0.00 0.00 0.663.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.62 0.00 0.00 0.76 40.38 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.97 0.27 0.00 1.08 5 0.350.00 0.00 0.00 0.32 0.00 0.00 0.27 0.27 1.37 0.35 0.35 0.75 6 0.53 0.380.00 0.00 0.49 0.00 0.00 0.28 0.42 1.47 0.36 0.45 0.75 7 0.54 0.29 0.000.00 0.41 0.29 0.00 0.27 0.39 1.64 0.49 0.58 0.79 8 0.47 0.32 0.00 0.250.57 0.25 0.00 0.51 0.42 1.85 0.57 0.69 0.79 10 0.47 0.35 0.25 0.36 0.620.34 0.00 0.74 0.51 1.82 1.12 1.07 1.14 12 0.88 0.00 0.41 0.52 0.94 0.360.35 0.74 1.28 2.26 0.80 1.09 1.99 14 1.00 0.33 0.51 0.68 1.26 0.36 0.410.98 1.28 2.45 1.26 1.16 2.25 16 1.01 0.39 0.59 0.62 1.40 0.52 0.37 1.261.22 2.38 1.37 1.03 2.31 20 1.08 0.64 0.79 0.59 1.25 0.76 0.26 1.43 0.712.42 1.64 0.80 1.38 24 0.81 0.44 0.55 0.49 0.76 0.95 0.00 0.68 0.61 1.751.39 0.69 0.84 28 0.97 0.47 0.56 0.56 0.48 1.22 0.00 1.00 0.93 1.74 1.040.87 0.59 32 0.82 0.34 0.31 0.33 0.00 1.14 0.00 1.03 1.21 0.70 0.59 0.610.33 36 0.47 0.32 0.00 0.00 0.00 0.66 0.00 0.65 0.64 0.41 0.32 0.46 0.0048 0.27 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 600.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 72 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Max 1.1 0.60.8 0.7 1.4 1.2 0.4 1.4 1.3 2.4 1.6 1.2 2.3 ng/ml Tmax H 20.0 20.0 20.014.0 16.0 28.0 14.0 20.0 12.0 14.0 20.0 14.0 16.0 AUC0-t 30.0 11.5 12.312.5 21.8 23.8 6.1 31.9 31.4 61.4 38.8 32.9 43.5 H · ng/ml F AUC 86.657.0 73.3 81.9 80.3 105.2 24.8 71.1 66.6 131.5 112.6 115.5 143.7 F Cmax53.1 53.3 72.2 49.2 79.9 100.6 23.9 42.9 41.0 89.3 72.3 104.8 120.8

TABLE 20 GR-02 Mean BFB-520 Plasma Concentrations and Parameters GR02BFB-520 PLASMA CONCENTRATIONS GR02 and AUCo-t Hours MEAN Sd Sm CV % 00.00 0.25 0.00 0.5 0.00 1 0.00 1.5 0.00 2 0.00 2.5 0.03 0.13 0.07 375.283 0.07 0.20 0.13 280.02 3.5 0.11 0.27 0.19 254.72 4 0.21 0.40 0.29191.24 5 0.31 0.40 0.27 130.19 6 0.39 0.42 0.28 106.04 7 0.44 0.45 0.30102.76 8 0.52 0.49 0.31 94.19 10 0.68 0.51 0.41 75.52 12 0.90 0.68 0.5175.73 14 1.07 0.70 0.53 65.30 16 1.11 0.69 0.54 61.68 20 1.06 0.59 0.4755.93 24 0.77 0.45 0.31 59.06 28 0.80 0.45 0.34 55.61 32 0.57 0.41 0.3371.69 36 0.30 0.28 0.24 92.16 48 0.02 0.00 60 0.00 72 0.00 Max ng/ml1.27 0.63 0.47 49.77 Tmax H 17.54 4.46 3.56 25.42 AUC0-t 27.53 15.9912.65 58.08 H · ng/ml F AUC 88.46 33.92 27.56 38.35 F Cmax 69.48 29.5824.00 42.56

See FIG. 11.

TABLE 21 Comparison of MR32, GR-01, and GR-02 BFB-520 PlasmaConcentrations. MR32 GR01 and GR02 Mean BFB-520 Plasma Concentrations(ng/ml) Hours MR32-MEAN GR01-Mean GR02-Mean 0 0.00 0.00 0.00 0.25 0.000.00 0.00 0.5 0.00 0.00 0.00 1 0.42 0.00 0.00 1.5 0.81 0.00 0.00 2 1.040.04 0.00 2.5 1.21 0.22 0.03 3 1.46 0.49 0.07 3.5 1.49 0.65 0.11 4 1.550.77 0.21 5 1.59 0.89 0.31 6 1.55 0.87 0.39 7 1.44 0.94 0.44 8 1.51 1.070.52 10 1.48 1.10 0.68 12 1.21 1.04 0.90 14 1.40 1.11 1.07 16 1.01 1.081.11 20 0.85 0.96 1.06 24 0.50 0.63 0.77 28 0.35 0.63 0.80 32 0.15 0.370.57 36 0.05 0.25 0.30 48 0.00 0.03 0.02 60 0.00 0.00 0.00 72 0.00 0.000.00 CMax ng/ml 1.9 1.4 1.27 Tmax H 6.9 12.5 17.5 AUC0-8 H · ng/ml 9.74.5 1.66 AUC0-12 15.4 8.8 4.4 H · ng/ml AUC0-t H · ng/ml 30.3 27.5 27.5F AUC REF 96.1 88.5 F Cmax REF 80.5 69.5

See FIG. 12.

TABLE 22 Comparison of MR32, GR-01, and GR-02 BFB-520 PlasmaConcentrations - Rates of Increase and Decrease. MR32 GR01 and GR02 MeanBFB-520 Plasma Conc. Rates of Increase and Decrease (ng/ml)/H HoursMR32-RATE GR01-RATE GR02-RATE 0 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.50.00 0.00 0.00 1 0.84 0.00 0.00 1.5 0.77 0.00 0.00 2 0.46 0.09 0.00 2.50.34 0.35 0.07 3 0.49 0.54 0.07 3.5 0.07 0.31 0.07 4 0.11 0.24 0.20 50.04 0.13 0.10 6 0.00 0.00 0.08 7 0.00 0.07 0.04 8 0.07 0.13 0.08 100.00 0.01 0.08 12 0.00 0.00 0.11 14 0.10 0.04 0.09 16 0.00 0.00 0.02 200.00 0.00 0.00 24 0.00 0.00 0.00 28 0.00 0.00 0.01 32 0.00 0.00 0.00 360.00 0.00 0.00 VMax (ng/ml)/H 0.84 0.54 0.20 Time of VMax 1.00 3.00 4.00TEST/MR32 REF 0.64 0.24

During each time interval (dt) the plasma concentration (C_(p)) ofBFB-520 increases or decreases. From t=0 to T_(max), the rate ofincrease V_(max)=d(C_(p))/dt. After the V_(max), the rates aredecreasing. See FIG. 13.

Example 10: Predicted Plasma Concentrations of MIN-101 and BFB-520 atSteady State in MR32

And GR-01 Tablets (32 and 64 mg)

TABLE 23 Predicted Plasma Concentrations of MIN-101 at Steady State inMR32 and GR-01, 32 mg Tablets MR32 and GR01 Mean MIN-101 at Steady-StatePlasma Concentrations (ng/ml) HOURS MR32SS GR01 SS 72 3.32 6.45 72.59.68 6.20 73 22.62 6.30 73.5 26.74 6.96 74 26.78 11.23 74.5 27.14 16.9775 24.39 20.59 75.5 22.54 20.89 76 21.96 20.58 77 23.38 18.91 78 16.8315.30 79 13.34 13.96 80 11.89 12.95 82 13.49 13.53 84 13.66 14.02 8610.97 13.80 88 8.24 12.32 92 4.44 6.75 96 3.32 6.46 CMaxSS ng/ml 27.120.9 CMinSS 3.32 6.46 TmaxSS H 2.50 3.5 AUC72-96 H · ng/ml 292.6 287.6 FAUC REF 98.3 F Cmax REF 76.9

See FIG. 14.

TABLE 24 Predicted Plasma Concentrations of BFB-520 at Steady State inMR32 and GR-01, 32 mg Tablets MR32 and GR01 BFB-520 at Steady-StatePlasma Concentrations (ng/ml) HOURS MR32 SS GR01 SS 72 0.50 0.66 72.50.44 0.63 73 0.81 0.60 73.5 1.15 0.57 74 1.35 0.58 74.5 1.48 0.72 751.70 0.97 75.5 1.71 1.10 76 1.89 1.42 77 1.74 1.27 78 1.66 1.21 79 1.541.24 80 1.66 1.46 82 1.53 1.31 84 1.26 1.29 86 1.41 1.25 88 1.03 1.19 920.85 1.03 96 0.50 0.86 CMaxSS ng/ml 1.89 1.46 CMinSS 0.50 0.66 TmaxSS H4.00 3.5 AUC72-96 29.1 26.3 H · ng/ml F AUC REF 90.6 F Cmax REF 77.2

See FIG. 15.

TABLE 25 Predicted Plasma Concentrations of MIN-101 at Steady State inMR32 and GR-01, 64 mg Tablets MR32 and GR01 64 mg at Steady-State MIN101Plasma Concentrations (ng/ml) HOURS MR32SS GR01 SS 72 6.64 12.90 72.519.36 12.40 73 45.24 12.60 73.5 53.47 13.93 74 53.55 22.46 74.5 54.2833.94 75 48.77 41.18 75.5 45.07 41.77 76 43.93 41.17 77 46.76 37.82 7833.65 30.60 79 26.69 27.92 80 23.78 25.90 82 26.97 27.06 84 27.31 28.0586 21.94 27.61 88 16.49 24.64 92 8.89 13.49 96 6.64 12.93 CMaxSS ng/ml54.28 41.77 CMinSS 6.64 12.93 TmaxSS H 2.50 3.50 AUC72-96 585.2 577.6 H· ng/ml F AUC REF 98.7 F Cmax REF 76.9

See FIG. 16.

TABLE 26 Predicted Plasma Concentrations of BFB-520 at Steady State inMR32 and GR-01, 64 mg Tablets MR32 and GR01 64 mg at Steady-StateBFB-520 Plasma Concentrations (ng/ml) HOURS MR32SS GR01 SS 72 0.99 1.3272.5 0.88 1.27 73 1.63 1.20 73.5 2.31 1.13 74 2.69 1.16 74.5 2.96 1.4575 3.40 1.93 75.5 3.41 2.19 76 3.79 2.84 77 3.48 2.54 78 3.33 2.41 793.07 2.48 80 3.32 2.92 82 3.05 2.62 84 2.51 2.57 86 2.83 2.49 88 2.052.37 92 1.70 2.05 96 0.99 1.32 CMaxSS ng/ml 3.79 2.92 CMinSS 0.99 1.32TmaxSS H 4.00 8.00 AUC72-96 H · ng/ml 58.1 52.8 F AUC REF 90.8 F CmaxREF 77.2

See FIG. 17.

Example 11: Predicted Plasma Concentrations of MIN-101 and BFB-520 atSteady State in MR32 and GR-02 Tablets (32 and 64 mg)

TABLE 27 Predicted Plasma Concentrations of MIN-101 at Steady State inMR32 and GR-02, 32 mg Tablets MR32 and GR02 Mean MIN-101 at Steady-StatePlasma Concentrations (ng/ml) HOURS MR32SS GR02 SS 72 3.32 8.26 72.59.68 7.88 73 22.62 7.46 73.5 26.74 7.23 74 26.78 7.37 74.5 27.14 8.32 7524.39 9.22 75.5 22.54 10.37 76 21.96 12.08 77 23.38 11.87 78 16.83 10.4979 13.34 9.74 80 11.89 10.56 82 13.49 10.66 84 13.66 15.38 86 10.9713.87 88 8.24 12.09 92 4.44 7.17 96 3.32 8.27 CMaxSS ng/ml 27.1 15.4CMinSS 3.32 7.17 TmaxSS H 2.50 12 AUC72-96 292.6 248.3 H · ng/ml F AUCREF 84.9 F Cmax REF 56.7

See FIG. 18.

TABLE 28 Predicted Plasma Concentrations of BFB-520 at Steady State inMR32 and GR-02, 32 mg Tablets MR32 and GR02 Mean MIN-101 at Steady-StatePlasma Concentrations (ng/ml) HOURS MR32SS GR02 SS 72 0.50 0.79 72.50.44 0.76 73 0.81 0.72 73.5 1.15 0.67 74 1.35 0.63 74.5 1.48 0.63 751.70 0.63 75.5 1.71 0.63 76 1.89 1.04 77 1.74 0.75 78 1.66 0.78 79 1.530.78 80 1.66 1.10 82 1.53 0.92 84 1.26 1.20 86 1.41 1.22 88 1.03 1.23 920.85 1.13 96 0.50 0.79 CMaxSS ng/ml 1.89 1.23 CMinSS 0.50 0.79 TmaxSS H4.00 16.00 AUC72-96 H · ng/ml 29.1 23.6 F AUC REF 81.4 F Cmax REF 64.8

See FIG. 19.

TABLE 29 Predicted Plasma Concentrations of MIN-101 at Steady State inMR32 and GR-02, 64 mg Tablets MR32 and GR02 64 mg at Steady-State MIN101Plasma Concentrations (ng/ml) HOURS MR32SS GR02 SS 72 6.64 16.53 72.519.36 15.77 73 45.24 14.93 73.5 53.47 14.45 74 53.55 14.75 74.5 54.2816.64 75 48.77 18.44 75.5 45.07 20.74 76 43.93 24.16 77 46.76 23.75 7833.65 20.98 79 26.69 19.49 80 23.78 21.12 82 26.97 21.32 84 27.31 30.7786 21.94 27.73 88 16.49 24.18 92 8.89 14.35 96 6.64 16.53 CMaxSS ng/ml54.28 30.77 CMinSS 6.64 14.35 TmaxSS H 2.50 12.00 AUC72-96 585.2 498.6 H· ng/ml F AUC REF 85.2 F Cmax REF 56.7

See FIG. 20.

TABLE 30 Predicted Plasma Concentrations of BFB-520 at Steady State inMR32 and GR-02, 64 mg Tablets MR32 and GR02 64 mg at Steady-StateBFB-520 Plasma Concentrations (ng/ml) HOURS MR32SS GR02 SS 72 0.99 1.5872.5 0.88 1.52 73 1.63 1.43 73.5 2.31 1.35 74 2.69 1.27 74.5 2.96 1.2675 3.40 1.26 75.5 3.41 1.27 76 3.79 2.07 77 3.48 1.50 78 3.33 1.57 793.07 1.57 80 3.32 2.20 82 3.05 1.83 84 2.51 2.40 86 2.83 2.44 88 2.052.45 92 1.70 2.25 96 0.99 1.58 CMaxSS ng/ml 3.79 2.45 CMinSS 0.99 1.58TmaxSS H 4.00 16.00 AUC72-96 58.1 47.4 H · ng/ml F AUC REF 81.6 F CmaxREF 64.8

See FIG. 21.

Examples 12-15 detail an evaluation of the PK profile of the GR-01formulation in healthy CYP2D6 EM male and female subjects in fed andfasted states (or predictions thereof). Subjects who completed part 1 ofthe study (evaluation of the PK profile of MIN-101 and its metaboliteBFB-520 in the GR-01, GR-02, and MR32 formulations) returned andreceived a further single oral dose of GR-01 under fed or fastedconditions to allow the assessment of food effect by comparison of thePK properties to those obtained in part 1 (Examples 9-12). There was awash-out period of 14±2 days after part 1.

Example 12: In Vivo Pharmacokinetic Analysis of MIN-101 in CR GR-01Tablets in Subjects in Fed Versus Fasted States. (Tau=72 h)

Fed State—12 subjects (cross-over)

Geo Mean C_(max): 19.70 ng/mL

T_(max): 12.00 H

AUC_((0-tau)): 269.19 ng·H/mL

TABLE 31 CR GR-01 Individual MIN-101 Plasma Concentrations andParameters (Fed State) GR01 FED MIN-101 PLASMA CONCENTRATIONS (ng/ml)and AUCo-t (H · ng/ml) 1- 2- 3- 5- 7- 8- 9- 10- 11- 12- GR01 MIN- MIN-MIN- MIN- 6-MIN- MIN- MIN- MIN- MIN- MIN- MIN- 13-MIN- Hours 101 101 101101 101 101 101 101 101 101 101 101 0 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 1.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 20.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2.5 0.000.00 6.78 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 3 0.00 0.00 11.160.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 6.11 3.5 0.00 0.00 11.00 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 7.61 4 0.00 0.00 14.38 0.00 0.00 0.290.00 0.00 0.00 0.00 0.00 6.83 5 0.00 0.00 14.05 23.02 0.00 12.75 0.000.00 0.53 0.00 0.00 6.91 6 0.00 18.46 13.78 13.78 0.00 16.81 0.00 0.0023.86 0.00 0.00 6.14 7 0.00 18.93 12.69 10.82 0.00 11.65 0.00 0.00 18.1615.83 0.00 5.15 8 0.00 12.77 6.36 9.89 0.00 10.59 0.00 0.00 17.78 14.650.00 4.24 10 3.52 7.72 3.90 11.82 0.00 7.97 0.00 23.19 14.80 11.23 0.006.86 12 35.98 6.41 9.71 6.41 19.91 13.62 0.00 8.39 14.32 12.39 24.8412.40 14 12.33 3.95 7.26 2.94 11.75 13.61 0.00 5.32 16.35 17.47 12.748.83 16 14.86 9.72 10.01 1.55 8.72 8.89 0.00 6.30 20.47 12.39 7.55 6.0420 7.18 4.51 4.76 0.52 6.95 9.42 4.24 5.28 11.74 11.01 14.00 4.23 246.70 2.72 5.92 0.00 12.81 5.57 10.84 30.76 9.83 10.33 26.27 6.75 28 7.172.40 4.48 0.00 18.56 5.20 5.81 16.53 5.52 7.82 21.35 4.34 32 6.56 2.192.84 0.00 10.82 3.49 2.32 10.29 3.17 3.44 14.17 3.32 36 5.97 1.15 1.610.00 5.35 2.19 0.92 3.93 1.80 1.85 6.78 2.42 48 1.66 0.39 0.90 0.00 1.570.67 0.00 0.83 0.50 0.47 0.91 0.59 60 0.00 0.00 0.35 0.00 0.63 0.33 0.000.00 0.31 0.00 0.00 0.36 72 0.00 0.00 0.00 0.00 0.30 0.00 0.00 0.00 0.000.00 0.00 0.00 CMax 36.0 18.9 14.4 23.0 19.9 16.8 10.8 30.8 23.9 17.526.3 12.4 ng/ml Tmax H 12.0 7.0 4.0 5.0 12.0 6.0 24.0 24.0 6.0 14.0 24.012.0 AUC0-t 305.0 177.2 241.3 108.5 347.8 272.9 92.2 367.3 359.7 303.5444.8 210.2 H · ng/ml F AUC 108.3 80.8 104.8 35.0 132.3 106.2 43.1 102.8124.2 70.5 159.4 74.1 F Cmax 174.7 87.9 113.6 114.2 127.4 131.5 60.0109.1 132.2 65.5 93.8 97.7

TABLE 32 CR GR-01 Mean MIN-101 Plasma Concentrations and Parameters (FedState) GR01 FED MIN-101 PLASMA CONCENTRATIONS GR01 and AUCo-t Hours MEANSd Sm CV % 0 0.00 0.25 0.00 0.5 0.00 1 0.00 1.5 0.00 2 0.00 2.5 0.571.96 1.04 346.41 3 1.44 3.53 2.40 245.26 3.5 1.55 3.69 2.59 238.14 41.79 4.42 2.94 246.80 5 4.77 7.77 6.27 162.90 6 7.74 9.01 8.00 116.41 77.77 7.71 6.91 99.30 8 6.36 6.59 5.65 103.62 10 7.58 6.94 5.20 91.54 1213.70 9.54 6.71 69.63 14 9.38 5.54 4.66 59.09 16 8.88 5.51 3.85 62.03 207.04 3.93 3.13 55.89 24 10.71 9.09 6.31 84.89 28 8.26 6.76 5.27 81.78 325.22 4.30 3.50 82.42 36 2.83 2.17 1.79 76.52 48 0.71 0.52 0.39 73.23 600.16 0.22 0.19 133.11 72 0.03 0.09 0.05 346.41 CMax ng/ml 20.89 7.485.91 35.83 Tmax H 12.50 7.65 6.00 61.16 AUC0-t 269.19 107.53 86.11 39.95H · ng/ml F AUC 95.14 36.15 28.68 38.00 F Cmax 108.97 31.40 23.32 28.81

See FIG. 22

Fasted State—12 subjects (cross-over)

Geo Mean C_(max): 18.82 ng/mL

Median T_(max): 4.50 H

AUC_((0-tau)): 284.52 ng·H/mL

TABLE 33 CR GR-01 Individual MIN-101 Plasma Concentrations andParameters (Fasted State) GR01 FASTED MEAN MIN-101 PLASMA CONCENTRATIONS(ng/ml) and AUCo-t (H · ng/ml) 1- 2- 3- 5- 7- 8- 9- 10- 11- 12- GR01MIN- MIN- MIN- MIN- 6-MIN- MIN- MIN- MIN- MIN- MIN- MIN- 13-MIN- Hours101 101 101 101 101 101 101 101 101 101 101 101 0 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.004.22 0.00 0.00 0.00 1.5 0.00 0.00 6.26 0.00 0.00 0.00 0.38 0.00 0.420.00 0.00 7.98 2 3.83 5.42 10.68 2.50 0.00 0.00 13.23 0.00 8.71 16.030.48 8.14 2.5 15.95 13.82 11.87 12.14 0.00 3.45 12.42 3.00 12.78 24.1723.30 7.62 3 17.85 17.61 11.10 13.88 0.39 12.78 11.08 24.02 12.98 16.6828.00 10.13 3.5 15.56 21.53 10.97 12.31 6.52 10.89 10.94 28.19 13.6025.78 24.01 12.18 4 20.60 19.02 8.23 11.96 15.23 9.53 8.04 22.91 17.6424.78 22.59 11.30 5 17.05 17.24 6.66 14.68 15.63 8.44 14.90 17.95 12.9224.46 12.86 12.69 6 15.26 14.41 6.89 13.19 13.39 6.06 12.36 11.72 7.6219.24 5.64 10.42 7 9.61 11.29 6.28 12.62 10.60 4.71 11.51 13.95 6.7017.83 9.72 9.08 8 7.46 7.20 5.58 11.86 10.51 3.51 8.19 16.53 13.39 14.165.82 8.62 10 4.30 5.10 12.66 11.69 6.19 2.71 18.08 17.00 18.05 8.6813.19 10.59 12 9.45 5.59 10.24 20.15 7.24 3.05 12.22 13.92 16.31 11.1513.39 12.47 14 13.11 10.14 12.01 17.73 7.12 3.52 12.65 12.02 14.42 11.6720.32 6.36 16 10.98 6.35 12.59 16.88 6.40 3.18 7.19 11.25 13.43 13.2919.44 6.02 20 5.54 3.88 4.69 8.36 4.95 2.65 2.44 7.99 6.52 9.76 5.923.23 24 5.57 1.94 3.21 6.73 6.31 2.38 2.90 12.21 3.90 10.97 3.63 7.08 284.31 1.64 3.18 2.55 3.91 2.35 1.47 7.67 3.79 10.31 0.54 5.80 32 3.501.56 2.73 1.16 3.55 5.90 0.66 3.59 2.79 7.59 0.67 3.46 36 2.37 1.06 1.340.54 2.14 12.25 0.00 1.06 0.56 3.73 0.37 3.60 48 1.33 0.73 0.28 0.002.04 2.55 0.00 0.00 0.00 0.56 0.00 1.76 60 0.00 0.48 0.00 0.00 1.33 1.330.00 0.00 0.00 0.00 0.00 0.46 72 0.00 0.69 0.00 0.00 0.41 0.44 0.00 0.000.00 0.00 0.00 0.27 CMax 20.6 21.5 12.7 20.2 15.6 12.8 18.1 28.2 18.126.7 28.0 12.7 ng/ml Tmax H 4.0 3.5 10.0 12.0 5.0 3.0 10.0 3.5 10.0 3.03.0 5.0 AUC0-t 281.6 219.3 230.1 309.7 262.8 257.0 213.8 357.2 289.7430.4 279.0 283.6 H · ng/ml

TABLE 34 CR GR-01 Mean MIN-101 Plasma Concentrations and Parameters(Fasted State) GR01 FASTED MIN-101 PLASMA GR01 CONCENTRATIONS and AUCo-tHours MEAN Sd Sm CV % 0 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.50.00 0.00 0.00 0.00 1 0.35 1.22 0.65 346.41 1.5 1.25 2.77 1.95 220.78 25.75 5.57 4.67 96.91 2.5 11.71 7.46 5.46 63.69 3 15.54 7.84 6.08 50.453.5 16.04 7.01 5.89 43.68 4 15.99 6.08 5.27 38.00 5 14.62 4.60 3.2631.47 6 11.35 4.17 3.35 36.70 7 10.33 3.58 2.64 34.63 8 9.39 3.93 3.2541.81 10 10.69 5.39 4.42 50.45 12 11.26 4.66 3.48 41.34 14 11.76 4.673.33 39.73 16 10.58 4.87 3.96 46.01 20 5.49 2.33 1.85 42.48 24 5.57 3.302.58 59.31 28 3.96 2.80 2.04 70.67 32 3.10 2.06 1.50 66.68 36 2.42 3.332.05 137.50 48 0.77 0.92 0.77 119.51 60 0.30 0.51 0.40 171.48 72 0.150.24 0.20 159.83 CMax ng/ml 19.59 5.74 4.61 29.30 Tmax H 6.00 3.43 3.0057.19 AUC0-t 284.52 60.83 41.49 21.38 H · ng/ml

See FIG. 23

TABLE 35 CR GR-01 Mean MIN-101 Plasma Concentrations and Parameters (Fedversus Fasted State) GR01 FOOD EFFECT Mean MIN-101 MIN101 PlasmaConcentrations (ng/ml) Hours GR01 FED GR01 FASTED 0 0.00 0.00 0.25 0.000.00 0.5 0.00 0.00 1 0.00 0.35 1.5 0.00 1.25 2 0.00 5.75 2.5 0.57 11.713 1.44 15.54 3.5 1.55 16.04 4 1.79 15.99 5 4.77 14.62 6 7.74 11.35 77.77 10.33 8 6.36 9.39 10 7.58 10.69 12 13.70 11.26 14 9.38 11.76 168.88 10.58 20 7.04 5.49 24 10.71 5.57 28 8.26 3.96 32 5.22 3.10 36 2.832.42 48 0.71 0.77 60 0.16 0.30 72 0.03 0.15 Max ng/ml 20.9 19.6 Tmax H12.5 6.0 AUC0-t 269.2 284.5 H · ng/ml F AUC 95.14 REF F Cmax 108.97 REF

Relative bioavailability of MIN-101 in GR-01 formulation in fed versusfasted states:

F % C_(max): 108.97%

F % AUC_((0-tau)): 95.14%

See FIG. 24

Example 13: In Vivo Pharmacokinetic Analysis of BFB-520 in CR GR-01Tablets in Subjects in Fed Versus Fasted States. (Tau=72 h)

Fed State—12 subjects (cross-over)

Geo Mean C_(max): 1.54 ng/mL

Median T_(max): 18.00 H

AUC_((0-tau)): 30.12 ng·H/mL

TABLE 36 CR GR-01 Individual BFB-520 Plasma Concentrations andParameters (Fed State) GR01 FED BFB-520 PLASMA CONCENTRATIONS (ng/ml)and AUCo-t (H · ng/ml) 1- 2- 3- 5- 7- 8- 9- 10- 11- 12- GR01 BFB- BFB-BFB- BFB- 6-BFB- BFB- BFB- BFB- BFB- BFB- BFB- 13-BFB- Hours 520 520 520520 520 520 520 520 520 520 520 520 0 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 1.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 20.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2.5 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 3 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 3.5 0.00 0.00 0.33 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 4 0.00 0.00 0.48 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.27 5 0.00 0.00 0.64 0.46 0.00 0.82 0.00 0.000.00 0.00 0.00 0.32 6 0.00 0.46 0.76 0.61 0.00 1.19 0.00 0.00 0.90 0.000.00 0.34 7 0.00 0.90 1.09 0.64 0.00 1.28 0.00 0.00 1.19 1.00 0.00 0.388 0.00 1.06 0.83 0.90 0.00 1.53 0.00 0.00 1.54 1.77 0.00 0.42 10 0.001.08 0.70 1.07 0.00 1.44 0.00 0.51 1.57 1.74 0.00 0.67 12 1.48 0.52 0.690.79 0.79 1.82 0.00 1.14 1.50 1.64 1.08 0.67 14 1.56 0.46 0.62 0.52 0.872.20 0.00 1.51 2.06 2.53 1.38 0.83 16 1.03 0.79 0.76 0.39 1.15 1.69 0.001.26 2.13 2.28 0.95 0.85 20 0.87 0.85 0.64 0.00 1.02 2.15 0.00 1.43 2.362.66 0.83 0.72 24 0.65 0.58 0.46 0.00 1.75 1.15 0.00 2.95 1.08 1.88 1.250.41 28 1.14 0.48 0.63 0.00 1.31 1.13 0.81 2.46 1.42 1.93 1.86 0.56 320.89 0.30 0.32 0.00 0.90 0.90 0.43 2.35 0.74 0.95 1.36 0.43 36 0.60 0.000.00 0.00 0.26 0.58 0.00 0.95 0.36 0.60 0.78 0.34 48 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 60 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 72 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 Max 16 1.1 1.1. 1.1 1.8 2.2 0.8 2.9 2.4 2.7 1.9 0.9ng/ml Tmax H 14.0 10.0 7.0 10.0 28.0 14.0 28.0 24.0 20.0 20.0 28.0 16.0AUC0-t 24.4 17.5 18.0 8.2 34.9 43.7 6.8 49.2 45.6 55.8 34.4 22.9 H ·ng/ml F AUC 104.2 94.2 112.0 26.1 177.5 230.2 34.5 112.5 126.5 137.5102.1 82.0 F CMax 130.3 84.3 132.0 59.3 170.1 199.6 63.4 163.9 128.4162.9 82.5 79.1

TABLE 37 CR GR-01 Mean BFB-520 Plasma Concentrations and Parameters (FedState) GR01 FED BFB-520 PLASMA GR01 CONCENTRATIONS and AUCo-t Hours MEANSd Sm CV % 0 0.00 0.25 0.00 0.5 0.00 1 0.00 0.00 0.00 #DIV/0! 1.5 0.000.00 0.00 #DIV/0! 2 0.00 0.00 0.00 #DIV/0! 2.5 0.00 0.00 0.00 #DIV/0! 30.00 0.00 0.00 #DIV/0! 3.5 0.03 0.09 0.05 346.41 4 0.06 0.15 0.10 244.575 0.19 0.30 0.25 159.98 6 0.35 0.43 0.36 120.06 7 0.54 0.53 0.48 98.36 80.67 0.69 0.60 102.84 10 0.73 0.65 0.54 88.88 12 1.01 0.53 0.43 52.69 141.22 0.78 0.65 64.14 16 1.08 0.67 0.50 61.50 20 1.14 0.86 0.68 75.79 241.01 0.78 0.54 77.24 28 1.18 0.72 0.54 77.24 32 0.83 0.63 0.46 75.80 360.42 0.36 0.31 85.11 48 0.01 60 0.00 72 0.00 Max ng/ml 1.69 0.73 0.6143.32 Tmax H 18.25 7.56 6.42 41.41 AUC0-t 30.12 16.26 13.82 53.98 H ·ng/ml F AUC 111.58 55.50 37.75 49.74 F Cmax 121.32 46.86 39.66 38.63

See FIG. 25

Fasted State—12 subjects (cross-over)

Geo Mean C_(max): 1.32 ng/mL

Median T_(max): 12.5 H

AUC_((0-tau)): 27.48 ng·H/mL

TABLE 38 CR GR-01 Individual BFB-520 Plasma Concentrations andParameters (Fasted State) GR01 FASTED BFB-520 PLASMA CONCENTRATIONS(ng/ml) and AUCo-t (H · ng/ml) 1- 2- 3- 5- 7- 8- 9- 10- 11- 12- GR01BFB- BFB- BFB- BFB- 6-BFB- BFB- BFB- BFB- BFB- BFB- BFB- 13-BFB Hours520 520 520 520 520 520 520 520 520 520 520 520 0 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 1.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 2 0.00 0.00 0.26 0.00 0.00 0.00 0.00 0.00 0.00 0.28 0.000.00 2.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 30.42 0.71 0.45 0.44 0.00 0.26 0.60 0.60 0.63 0.88 0.28 0.00 3.5 0.541.00 0.50 0.47 0.00 0.38 0.57 1.28 0.74 1.00 0.86 0.43 4 0.84 1.04 0.490.63 0.35 0.39 0.45 1.41 1.08 1.29 0.72 0.51 5 1.01 0.98 0.39 0.72 0.620.51 0.75 1.56 1.13 1.45 0.99 0.61 6 1.07 1.07 0.43 0.78 0.83 0.54 0.851.47 0.85 1.19 0.72 0.64 7 1.20 1.28 0.37 0.92 0.93 0.51 0.88 1.47 0.711.47 0.74 0.80 8 1.17 1.07 0.44 1.10 1.03 0.68 0.76 1.80 1.37 1.63 1.060.74 10 0.68 0.96 0.68 1.23 0.77 0.33 1.28 1.72 1.84 1.32 1.37 0.99 120.65 0.77 0.55 1.30 0.66 0.32 0.91 1.40 1.74 0.78 2.26 1.08 14 1.00 0.870.72 1.73 0.74 0.43 1.24 1.54 1.82 1.11 1.11 1.05 16 1.00 0.71 0.83 1.800.51 0.43 1.09 1.49 1.80 1.24 1.11 0.95 20 0.69 0.70 0.63 1.58 0.67 0.400.71 1.73 1.13 1.44 1.17 0.68 24 0.57 0.31 0.43 0.85 0.50 0.00 0.39 1.310.57 1.05 0.99 0.58 28 0.72 0.26 0.50 0.58 0.59 0.00 0.28 1.15 0.92 1.270.65 0.58 32 0.33 0.00 0.28 0.30 0.46 0.44 0.00 0.67 0.62 0.68 0.28 0.4336 0.29 0.00 0.00 0.00 0.38 1.10 0.00 0.28 0.00 0.51 0.00 0.42 48 0.000.00 0.00 0.00 0.00 0.33 0.00 0.00 0.00 0.00 0.00 0.00 60 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 72 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 Max 1.2 1.3 0.8 1.8 1.0 1.1 1.3 1.81.8 1.6 2.3 1.1 ng/ml Tmax H 7.0 7.0 16.0 16.0 8.0 36.0 10.0 8.0 10.08.0 12.0 12.0 AUC0-t 23.5 18.6 16.1 31.3 19.7 19.0 19.6 43.8 36.1 40.633.7 27.9 H · ng/ml

TABLE 39 CR GR-01 Mean BFB-520 Plasma Concentrations and Parameters(Fasted State) GR01 BFB-520 PLASMA CONCENTRATIONS GR01 and AUCo-t HoursMEAN Sd Sm CV % 0 0.00 0.25 0.00 0.5 0.00 1 0.00 1.5 0.00 2 0.04 0.100.07 233.68 2.5 0.22 0.25 0.22 112.01 3 0.49 0.23 0.17 45.99 3.5 0.650.35 0.27 53.37 4 0.77 0.36 0.31 47.35 5 0.89 0.36 0.29 40.77 6 0.870.29 0.22 33.50 7 0.94 0.35 0.28 37.58 8 1.07 0.39 0.29 36.81 10 1.100.45 0.36 40.79 12 1.04 0.55 0.43 53.43 14 1.11 0.42 0.31 37.58 16 1.080.45 0.34 41.52 20 0.96 0.43 0.38 45.29 24 0.63 0.36 0.28 57.32 28 0.630.36 0.26 57.90 32 0.37 0.23 0.18 60.48 36 0.25 0.33 0.25 133.52 48 0.030.09 0.05 346.41 60 0.00 72 0.00 Max ng/ml 1.43 0.43 0.37 30.06 Tmax H12.50 8.04 5.08 64.32 AUC0-t 27.48 9.46 8.07 34.41 H · ng/ml F AUC 96.1035.77 18.95 37.22 F Cmax 80.48 24.60 20.65 30.56

See FIG. 26

TABLE 40 CR GR-01 Mean BFB-520 Plasma Concentrations and Parameters (Fedversus Fasted State) GR01 BFB-520 PLASMA CONCENTRATIONS GR01 and AUCo-tHours MEAN Sd Sm CV % 0 0.00 0.25 0.00 0.5 0.00 1 0.00 1.5 0.00 2 0.040.10 0.07 233.68 2.5 0.22 0.25 0.22 112.01 3 0.49 0.23 0.17 45.99 3.50.65 0.35 0.27 53.37 4 0.77 0.36 0.31 47.35 5 0.89 0.36 0.29 40.77 60.87 0.29 0.22 33.50 7 0.94 0.35 0.28 37.58 8 1.07 0.39 0.29 36.81 101.10 0.45 0.36 40.79 12 1.04 0.55 0.43 53.43 14 1.11 0.42 0.31 37.58 161.08 0.45 0.34 41.52 20 0.96 0.43 0.38 45.29 24 0.63 0.36 0.28 57.32 280.63 0.36 0.26 57.90 32 0.37 0.23 0.18 60.48 36 0.25 0.33 0.25 133.52 480.03 0.09 0.05 346.41 60 0.00 72 0.00 Max ng/ml 1.43 0.43 0.37 30.06Tmax H 12.50 8.04 5.08 64.32 AUC0-t 27.48 9.46 8.07 34.41 H · ng/ml FAUC 96.10 35.77 18.95 37.22 F Cmax 80.48 24.60 20.65 30.56

Relative bioavailability of BFB-520 in GR-01 formulation in fed versusfasted states:

F % C_(max): 121.32%

F % AUC_((0-tau)): 111.58%

See FIG. 27

Example 14: Predicted Food Effect on Plasma Concentrations of MIN-101and BFB-520 at Steady State in GR-01 Tablets (32 mg)

Determination of elimination slopes from the mean plasma concentrationstime curves before numerical computations.

MIN-101

Fed State: K_(e)=0.119/H

Fasted State: K_(e)=0.082/H

BFB-520:

Fed State: from 14 H to 28 H during the flip flop phase K_(e)=0.014/H;post absorption K_(e)=0.233/H

Fasted State: from 14 H to 28 H during the flip flop phaseK_(e)=0.005545/H; post absorption K_(e)=0.1586/H

TABLE 41 Predicted Plasma Concentrations of MIN-101 at Steady State inGR-01, 32 mg Tablets (Fed and Fasted states) GR01 32 mg FED and FASTEDMIN-101 at Steady-State MIN101 Plasma Concentrations (ng/ml) HOURS GR01FED SS GR01 FASTED SS 72 11.45 6.45 72.5 10.70 6.20 73 10.09 6.30 73.59.50 6.96 74 8.95 11.23 74.5 9.00 16.97 75 9.39 20.59 75.5 9.04 20.89 7610.46 20.58 77 11.04 18.91 78 13.30 15.30 79 12.71 13.96 80 11.83 12.9582 11.04 13.53 84 16.70 14.02 86 11.53 13.80 88 10.57 12.32 92 8.09 6.7596 11.45 6.46 CMaxSS ng/ml 16.7 20.9 CMinSS 8.09 6.46 TmaxSS H 12.00 3.5AUC72-96 263.8 287.6 H · ng/ml F AUC 91.7 REF F Cmax 80.0 REF

See FIG. 28.

TABLE 42 Predicted Plasma Concentrations of BFB-520 at Steady State inGR-01, 32 mg Tablets (Fed and Fasted states) GR01 32 mg FED and FASTEDBFB-520 at Steady-State BFB-520 Plasma Concentrations (ng/ml) HOURS GR01FED SS GR01 FASTED SS 72 1.03 0.66 72.5 1.02 0.64 73 1.01 0.62 73.5 1.000.60 74 0.99 0.63 74.5 0.99 0.79 75 0.98 1.04 75.5 1.00 1.18 76 1.251.41 77 1.13 1.38 78 1.29 1.33 79 1.46 1.38 80 1.51 1.45 82 1.26 1.37 841.43 1.29 86 1.43 1.26 88 1.21 1.19 92 1.19 1.02 96 1.03 0.66 CMaxSSng/ml 1.51 1.45 CMinSS 1.03 0.66 TmaxSS H 8.00 8.00 AUC72-96 29.5 27.0 H· ng/ml F AUC 109.4 REF F Cmax 103.7 REF

See FIG. 29.

Example 15: Predicted Food Effect on Plasma Concentrations of MIN-101and BFB-520 at Steady State in GR-01 Tablets (64 mg)

Determination of elimination slopes from the mean plasma concentrationstime curves before numerical computations.

MIN-101

Fed State: K_(e)=0.119/H

Fasted State: K_(e)=0.082/H

BFB-520:

Fed State: from 14 H to 28 H during the flip flop phase K_(e)=0.014/H;post absorption K_(e)=0.233/H

Fasted State: from 14 H to 28 H during the flip flop phaseK_(e)=0.005545/H; post absorption K_(e)=0.1586/H

TABLE 43 Predicted Plasma Concentrations of MIN-101 at Steady State inGR-01, 64 mg Tablets (Fed and Fasted states) GR01 64 mg FED and FASTEDMIN-101 at Steady-State MIN101 Plasma Concentrations (ng/ml) HOURS GR01FED SS GR01 FASTED SS 72 22.91 12.90 72.5 21.41 12.40 73 20.17 12.6073.5 19.01 13.93 74 17.91 22.46 74.5 18.00 33.94 75 18.78 41.18 75.518.08 41.77 76 20.92 41.17 77 22.08 37.82 78 26.60 30.60 79 25.42 27.9280 23.65 25.90 82 22.08 27.06 84 33.41 28.05 86 23.05 27.61 88 21.1424.64 92 16.17 13.49 96 22.91 12.93 CMaxSS ng/ml 33.41 41.77 CMinSS16.17 12.93 TmaxSS H 12.00 3.50 AUC72-96 527.5 577.6 H · ng/ml F AUC91.3 REF F Cmax 80.0 REF

See FIG. 30.

TABLE 44 Predicted Plasma Concentrations of BFB-520 at Steady State inGR-01, 64 mg Tablets (Fed and Fasted states) GR01 64 mg FED and FASTEDBFB-520 at Steady-State BFB-520 Plasma Concentrations (ng/ml) HOURS GR01FED SS GR01 FASTED SS 72 2.06 1.32 72.5 2.04 1.28 73 2.02 1.24 73.5 2.001.21 74 1.99 1.26 74.5 1.97 1.58 75 1.95 2.09 75.5 1.99 2.37 76 2.502.82 77 2.27 2.77 78 2.57 2.66 79 2.92 2.76 80 3.01 2.91 82 2.51 2.75 842.87 2.57 86 2.86 2.52 88 2.42 2.37 92 2.38 2.03 96 2.06 1.32 CMaxSSng/ml 3.01 2.91 CMinSS 2.06 1.32 TmaxSS H 8.00 8.00 AUC72-96 59.0 54.1 H· ng/ml F AUC 109.1 REF F Cmax 103.7 REF

See FIG. 31.

Example 16: Description of 32 mg Gastro-Resistant CR Tablet (GR01/B-32mg)

The CR GR-01/B tablets are supplied as round (diameter 10 mm and R=10)tablets, free from visual defects. Each tablet contains 32 mg ofCompound (I). The complete statement of the components and quantitativecomposition of CR GR-01/B tablet is given in Table 45.

TABLE 45 Composition of CR GR-01/B 32 mg tablet GR-01/B-32 mgComponent/Ingredient mg/tablet % (w/w) MIN-101¹ 38.40 12.09 Hypromellose30.00 9.45 (METHOCEL ™ K100LV CR) Hypromellose 72.00 22.67 (Methocel ™K100M CR) Microcrystalline Cellulose 96.67 30.42 Lactose 60.00 18.89Silica Colloidal Anhydrous 1.50 0.47 Magnesium stearate 1.50 0.47Eudragit L30D55 15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.62 100.00¹Salt correction factor of 1.2 applied Example 17: Description of 64 mggastro-resistant CR tablet (GR-01/B-64 mg)

The CR GR-01/B tablets are supplied as round (diameter 10 mm and R=10)tablets, free from visual defects. Each tablet contains 64 mg ofCompound (I). The complete statement of the components and quantitativecomposition of CR GR-01/B tablet is given in Table 46.

TABLE 46 Composition of CR GR-01/B 64 mg tablet GR-01/B-64 mgComponent/Ingredient mg/tablet % (w/w) MIN-101¹ 76.8 24.14 Hypromellose30.00 9.45 (METHOCEL ™ K100LV CR) Hypromellose 72.00 22.67 (Methocel ™K100M CR) Microcrystalline Cellulose 77.40 24.37 Lactose 40.80 12.85Silica Colloidal Anhydrous 1.50 0.47 Magnesium stearate 1.50 0.47Eudragit L30D55 15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55 100.00¹Salt correction factor of 1.2 applied

Example 18: Comparison of GR-01 32 mg Tablet, GR-01/B 32 mg Tablet, andGR-01/B 64 mg Tablet

TABLE 47 Tablet Composition: GR01 vs GR01/B Ingredient GR01-32 mgGR01/B-32 mg GR01/B-64 mg Component mg/tablet % (w/w) mg/tablet % (w/w)mg/tablet % (w/w) MIN-101¹ 38.40 12.09 38.40 12.09 76.8 24.14Hypromellose 30.00 9.45 (Metolose ® 90SH 100 SR) Hypromellose 30.00 9.4530.00 9.45 (METHOCEL ™ K100LV CR) Hypromellose 72.00 22.67 72.00 22.6772.00 22.67 (Methocel ™ K100M CR) Microcrystalline Cellulose 95.10 29.9596.60 30.42 77.40 24.37 Lactose 60.00 18.89 60.00 18.89 40.80 12.85Silica Colloidal Anhydrous 1.50 0.47 1.50 0.47 1.50 0.47 Magnesiumstearate 3.00 0.94 1.50 0.47 1.50 0.47 Eudragit L30D55 15.0 4.72 15.04.72 15.0 4.72 Plasacryl HTP20 2.55 0.80 2.55 0.80 2.55 0.80 Total317.55 5.53 317.55 100.00 317.55 100.00 ¹Salt correction factor of 1.2applied

Example 19: Stability Data Experiments: Comparison of GR-01 and GR-01/B32 mg Tablets

“Impurity A,” “2-isomer,” and “PMIC” refer to impurities from themanufacturing process for MIN-101.

TABLE 48 Stability data at 25° C./60% RH Product MIN-101 ProductManufacturer: Amatsi Aquitaine Name: API Manufacturer: PCAS Strength: 32mg Container Closure: TEKNIFLEX ® VPOA 10200 and Storage 25° C./60% RHaluminum blister packs Condition: Stability Interval (Months) TestInitial 1 3 6 9 12 GR01 tablets Related Sub. (%) Impurity A <LOQ 0.020.03 0.04 0.03 <LOQ 2-isomer <LOQ <LOQ <LOQ 0.02 <LOQ <LOQ PMIC 0.080.13 0.18 0.20 0.24 0.26 Unspecified <0.1% <0.1% RRT0.67: 0.11 RRT0.67:RRT 0.67: RRT 0.67: imp. each each 0.12 0.12 0.15 Total 0.15 0.29 0.460.51 0.52 0.59 impurities GR01/B tablets Related Sub. (%) Impurity A NDND ND ND 2-isomer 0.07 0.07 0.07 0.07 PMIC 0.09 0.11 0.15 0.16Unspecified <0.1% <0.1% <0.1% each <0.1% each imp. each each Total 0.260.29 0.37 0.38 impurities

TABLE 49 Stability data at 40° C./75% RH Product Name: ProductManufacturer: Amatsi Aquitaine Strength: MIN-101 API Manufacturer: PCASStorage 32 mg Container Closure: TEKNIFLEX ® VPOA 10200 and Condition:40° C./75% RH aluminum blister packs Stability Interval (Months) TestInitial 1 3 6 GR01 tablets Related Sub. (%) Impurity A <LOQ 0.04 0.060.08 2-isomer <LOQ <LOQ <LOQ <LOQ PMIC 0.08 0.27 0.44 0.77 Unspecifiedimp. <0.1% each RRT0.67 = 0.12 RRT0.67: 0.18 RRT0.67: 0.24 Totalimpurities 0.15 0.57 0.94 1.46 GR01/B tablets Related Sub. (%) ImpurityA ND ND ND ND 2-isomer 0.07 0.07 0.07 0.06 PMIC 0.09 0.23 0.34 0.52Unspecified imp. <0.1% each <0.1% each RRT 0.67: 0.11 RRT 0.67: 0.15Total impurities 0.26 0.51 0.71 1.00

Example 20: In Vitro Dissolution Specifications for GR-01/B Tablets

TABLE 50 Specifications for GR-01/B tablets Acceptance Test MethodCriteria Dissolution (%) HPLC Report results (±10%) 2 hours  0.0% 4hours 24.1% 8 hours 59.2% 16 hours  88.6%

Example 21: Description of 32 mg Gastro-Resistant CR Tablet (GR-01/C-32mg)

The CR GR-01/C tablets are supplied as round (diameter 10 mm and R=10)tablets, free from visual defects. Each tablet contains 32 mg ofCompound (I). The complete statement of the components and quantitativecomposition of CR GR-01/C tablet is given in Table 51.

TABLE 51 Composition of CR GR-01/C 32 mg tablet GR-01/C-32 mgComponent/Ingredient mg/tablet % (w/w) MIN-101¹ 38.40 12.11 Hypromellose30.00 9.45 (METHOCEL ™ K100LV CR) Hypromellose 72.00 22.67 (Methocel ™K100M CR) Microcrystalline Cellulose 95.10 29.95 Lactose 60.00 18.89Silica Colloidal Anhydrous 1.50 0.47 Magnesium stearate 3.00 0.94Eudragit L30D55 15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55 100.00

Example 22: Description of 64 mg Gastro-Resistant CR Tablet (GR-01/C-64mg)

The CR GR-01/C tablets are supplied as round (diameter 10 mm and R=10)tablets, free from visual defects. Each tablet contains 64 mg ofCompound (I). The complete statement of the components and quantitativecomposition of CR GR-01/C tablet is given in Table 53.

TABLE 53 Composition of CR GR-01/C 64 mg tablet GR-01/C-64 mgComponent/Ingredient mg/tablet % (w/w) MIN-101¹ 76.8 24.19 Hypromellose30.00 9.45 (METHOCEL ™ K100LV CR) Hypromellose 72.00 22.67 (Methocel ™K100M CR) Microcrystalline Cellulose 75.90 23.91 Lactose 40.80 12.85Silica Colloidal Anhydrous 1.50 0.47 Magnesium stearate 3.00 0.94Eudragit L30D55 15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55 100.00

EQUIVALENTS AND INCORPORATION BY REFERENCE

The dosage forms, compositions and methods of the disclosure have beendescribed herein by reference to certain preferred embodiments. However,as particular variations thereon will become apparent to those skilledin the art, based on the disclosure set forth herein, the disclosure isnot to be considered as limited thereto.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. In the specification andclaims, the singular forms also include the plural unless the contextclearly dictates otherwise.

It is to be understood that at least some of the descriptions of thedisclosure have been simplified to focus on elements that are relevantfor a clear understanding of the disclosure, while eliminating, forpurposes of clarity, other elements that those of ordinary skill in theart will appreciate may also comprise a portion of the disclosure.However, because such elements are well known in the art, and becausethey do not necessarily facilitate a better understanding of thedisclosure, a description of such elements is not provided herein.

Further, to the extent that a method does not rely on the particularorder of steps set forth herein, the particular order of the stepsrecited in a claim should not be construed as a limitation on thatclaim.

All patents, patent applications, references and publications citedherein are fully and completely incorporated by reference as if setforth in their entirety. Such documents are not admitted to be prior artto the present disclosure.

What is claimed is:
 1. A gastro-resistant, controlled release dosageform, comprising: about 19 to about 29% w/w 1H-isoindol-1-one,2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-,hydrochloride, hydrate (1:1:2) (roluperidone hydrochloride); about 4 toabout 14% w/w of a low-viscosity, controlled-release grade hypromellose,that is about 19 to about 24% methoxy, about 7 to about 12%hydroxypropoxy, and wherein the hypromellose has a viscosity of about 80to about 120 mPa·s at 2% concentration in water at 20° C.; about 17 toabout 27% w/w of a controlled-release grade hypromellose, that is about19 to about 24% methoxy, about 7 to about 12% hydroxypropoxy, andwherein the hypromellose has a viscosity of about 80,000 to about120,000 mPa·s at 2% concentration in water at 20° C.; about 19 to about29% w/w microcrystalline cellulose; about 8 to about 18% w/w lactosemonohydrate; about 0.1 to about 4% w/w silica colloidal anhydrous; about0.1 to about 4% magnesium stearate; about 1 to about 10% w/w methacrylicacid and ethyl acrylate copolymer dispersion; and about 0.5 to about 5%w/w of an anti-tacking agent.
 2. The gastro-resistant, controlledrelease dosage form of claim 1, wherein the dosage form produces, uponoral administration to a subject, a plasma pharmacokinetic profile forthe BFB-520 metabolite of roluperidone hydrochloride which comprises aC_(max) that is below 4.0 ng/mL, below 3.5 ng/mL, below 3.0 ng/mL, orbelow 2.5 ng/mL.
 3. The gastro-resistant, controlled release dosage formof claim 1, wherein the dosage form comprises about 24% w/w ofroluperidone hydrochloride.
 4. The gastro-resistant, controlled releasedosage form of claim 1, comprising: about 24% w/w roluperidonehydrochloride; about 9% w/w of a low-viscosity, controlled-release gradehypromellose, that is about 19 to about 24% methoxy, about 7 to about12% hydroxypropoxy, and wherein the hypromellose has a viscosity ofabout 80 to about 120 mPa·s at 2% concentration in water at 20° C.;about 23% w/w of a controlled-release grade hypromellose, that is about19 to about 24% methoxy, about 7 to about 12% hydroxypropoxy, andwherein the hypromellose has a viscosity of about 80,000 to about120,000 mPa·s at 2% concentration in water at 20° C.; about 24% w/wmicrocrystalline cellulose; about 13% w/w lactose monohydrate; about0.5% w/w silica colloidal anhydrous; about 0.5% w/w magnesium stearate;about 5% w/w methacrylic acid and ethyl acrylate copolymer dispersion;and about 1% w/w of an anti-tacking agent.
 5. The gastro-resistant,controlled release dosage form of claim 1, comprising: about 24% w/wroluperidone hydrochloride; about 9% w/w of a low-viscosity,controlled-release grade hypromellose, that is about 19 to about 24%methoxy, about 7 to about 12% hydroxypropoxy, and wherein thehypromellose has a viscosity of about 80 to about 120 mPa·s at 2%concentration in water at 20° C.; about 23% w/w of a controlled-releasegrade hypromellose, that is about 19 to about 24% methoxy, about 7 toabout 12% hydroxypropoxy, and wherein the hypromellose has a viscosityof about 80,000 to about 120,000 mPa·s at 2% concentration in water at20° C.; about 24% w/w microcrystalline cellulose; about 13% w/w lactosemonohydrate; about 0.5% w/w silica colloidal anhydrous; about 1% w/wmagnesium stearate; about 5% w/w methacrylic acid and ethyl acrylatecopolymer dispersion; and about 1% w/w of an anti-tacking agent.
 6. Amethod of treating negative symptoms in a subject comprisingadministering to the subject the gastro-resistant, controlled releasedosage form of claim 1, wherein the subject has a diagnosis ofschizophrenia.
 7. The method of claim 6, wherein the subject having adiagnosis of schizophrenia has a CYP2D6 EM genotype.
 8. The method ofclaim 6, wherein the method further comprises reducing the risk of QTprolongation in the subject.
 9. A method of reducing a risk of QTprolongation in a subject when administering roluperidone hydrochlorideto said subject comprising administering to the subject thegastro-resistant, controlled release dosage form of claim
 1. 10. Themethod of claim 6, wherein the gastro-resistant, controlled releasedosage form is administered once daily.
 11. The method of claim 6,wherein the subject is in a fed state prior to oral administration ofthe dosage form.
 12. The method of claim 6, wherein the subject is in afasted state prior to oral administration of the dosage form.